Compounds containing phenyl linked to aryl or heteroaryl by an aliphatic- or heteroatom-containing linking group

ABSTRACT

This invention is directed to the pharmaceutical use of phenyl compounds, which are linked to an aryl moiety by various linkages, for inhibiting tumor necrosis factor. The invention is also directed to the compounds, their preparation and pharmaceutical compositions containing these compounds. Furthermore, this invention is directed to the pharmaceutical use of the compounds for inhibiting cyclic AMP phosphodiesterase.

This application is a continuation application of U.S. patentapplication Ser. No. 08/098,178, filed Jul. 28, 1993, now U.S. Pat. No.5,935,978, which, in turn, is a continuation-in-part application ofInternational Patent Application No. PCT/GB92/00153, filed Jan. 28,1992, designating the United States as a Receiving Office, nowabandoned.

FIELD OF THE INVENTION

This invention is directed to substituted phenyl compounds, theirpreparation, pharmaceutical compositions containing these compounds, andtheir pharmaceutical use in the treatment of disease states associatedwith proteins that mediate cellular activity.

Disease states associated with abnormally high physiological levels ofcytokines such as TNF are treatable according to the invention. TNF isan important pro-inflammatory cytokine which causes hemorrhagic necrosisof tumors and possesses other important biological activities. TNF isreleased by activated macrophages, activated T-lymphocytes, naturalkiller cells, mast cells and basophils, fibroblasts, endothelial cellsand brain astrocytes among other cells.

The principal in vivo actions of TNF can be broadly classified asinflammatory and catabolic. It has been implicated as a mediator ofendotoxic shock, inflammation of joints and of the airways, immunedeficiency states, allograft rejection, and in the cachexia associatedwith malignant disease and some parasitic infections. In view of theassociation of high serum levels of TNF with poor prognosis in sepsis,graft versus host disease and acute respiratory distress syndrome, andits role in many other immunologic processes, this factor is regarded asan important mediator of general inflammation.

TNF primes or activates neutrophils, eosinophils, fibroblasts andendothelial cells to release tissue damaging mediators. TNF alsoactivates monocytes, macrophages and T-lymphocytes to cause theproduction of colony stimulating factors and other pro-inflammatorycytokines such IL₁, IL₆, IL₈ and GM-CSF, which in some case mediate theend effects of TNF. The ability of TNF to activate T-lymphocytes,monocytes, macrophages and related cells has been implicated in theprogression of Human Immunodeficiency Virus (HIV) infection. In orderfor these cells to become infected with HIV and for HIV replication totake place the cells must be maintained in an activated state. Cytokinessuch as TNF have been shown to activate HIV replication in monocytes andmacrophages. Features of endotoxic shock such as fever, metabolicacidosis, hypotension and intravascular coagulation are thought to bemediated through the actions of TNF on the hypothalamus and in reducingthe anti-coagulant activity of vascular endothelial cells. The cachexiaassociated with certain disease states is mediated through indirecteffects on protein catabolism. TNF also promotes bone resorption andacute phase protein synthesis.

The discussion herein related to disease states associated with TNFinclude those disease states related to the production of TNF itself,and disease states associated with other cytokines, such as but notlimited to IL-1, or IL-6, that are modulated by associated with TNF. Forexample, a IL-1 associated disease state, where IL-1 production oraction is exacerbated or secreted in response to TNF, would therefore beconsidered a disease state associated with TNF. TNF-a and TNF-b are alsoherein referred to collectively as "TNF" unless specifically delineatedotherwise since theRE is a close structural homology between TNF-a(cachectin) and TNF-b (lymphotoxin) and each of them has a capacity toinduce similar biologic responses and bind to the same cellularreceptor.

Disease states associated with pathological conditions that aremodulated by inhibiting enzymes, which are associated with secondarycellular messengers, such as cyclic AMP phosphodiesterase are alsotreatable according to the invention cyclic AMP phosphodiesterase is animportant enzyme which regulates cyclic AMP levels and in turn therebyregulates other important biological reactions. The ability to regulatecyclic AMP phosphodiesterase, including type IV cyclic AMPphosphodiesterase, therefore, has been implicated as being capable oftreating assorted biological conditions.

In particular, inhibitors of type IV cyclic AMP phosphodiesterase havebeen implicated as being bronchodilators and asthma-prophylactic agentsand as agents for inhibiting eosinophil accumulation and of the functionof eosinophils, and for treating other diseases and conditionscharacterized by, or having an etiology involving, morbid eosinophilaccumulation. Inhibitors of cyclic AMP phosphodiesterase are alsoimplicated in treating inflammatory diseases, proliferative skindiseases and conditions associated with cerebral metabolic inhibition.

Reported Developments

Chemical Abstracts, 108(15), Apr. 11, 1988, abstract no. 131583ppertains to an abstract of Japanese Patent Application Publication No.JP-A-62 158,253 which discloses that a substituted phenyl compound offormula ##STR1## is a cardiotonic, but does not disclose or suggest thatthe compound inhibits cyclic AMP phosphodiesterase or TNF. JP-A-62158,253 also does not disclose or suggest that the moiety that is orthoto R¹ may be anything other than benzyloxy.

Chemical Abstracts, 99(6), Aug. 8, 1983, abstract no. 43556z pertains toan abstract of Japanese Patent Application Publication No. JP-A-5869,812 which discloses that a phenyl compound of formula ##STR2## is ahypoglycemic agent, but does not disclose or suggest that the compoundinhibits cyclic AMP phosphodiesterase or TNF. JP-A-5 869,812 also doesnot disclose or suggest that the benzamide moiety may be substituted byanything other than methoxy.

Panos Grarnmaticakis, Bull. Soc. Chim. Fr., 848-857 (1965) discloses aphenyl compound of the formula ##STR3## Grammaticakis examines theultraviolet and visible absorbances of compounds bearing differentsubstituents. Grammaticakis does not disclose or suggest that thecompound exhibits any pharmacological activity.

Ian W. Mathison, et al., J. Med. Chem., 16(4), 332-336 (1973), disclosesthat a phenyl compound of formula ##STR4## is a hypotensive agent, butdo not disclose or suggest that the compound inhibits cyclic AMPphosphodiesterase or TNF. Mathison, et al., also do not disclose orsuggest that the benzamide moiety may be substituted by anything otherthan methoxy.

European Patent Application Publication No. EP 232199 B1 discloses thatphenyl compounds of formula ##STR5## wherein R² is alkyl or mono- orpolycyclic cycloalkyl, exhibit anti-inflammatory and/or anti-allergicactivity. EP 232199 B1 does not disclose or suggest compounds whereinthe R² substituent is bonded to the phenyl moiety via an oxygen orsulfur atom.

European Patent Application Publication No. EP 470,805 A1 disclosesphenyl compounds of the formula ##STR6## wherein R may be C₃₋₇ alkyl,C₃₋₇ cycloalkyl or ##STR7## Z may be a bond; o is 1-4; a and b areindependently 1-3; and c is 0-2. EP 470.805 A1 discloses that thesecompounds are useful intermediates for preparing PDE IV inhibitors, butdoes not disclose or suggest that the compounds have any pharmacologicalactivity.

Japanese Patent Application Publication No. JP-A-0 4360847 disclosescompounds of the formula ##STR8## wherein R¹, R² and R³ may be the sameor different and may be optionally substituted lower alkyl(O); and A maybe optionally substituted aryl or 5-6 membered heterocyclyl group.JP-A-0 4360847 discloses that the compounds are useful intermediates forpreparing antimicrobial agents, but does not disclose or suggest thatthe compounds have any pharmacological activity.

WO Patent Application No. 92/12961 discloses that compounds of theformula ##STR9## inhibit cyclic AMP phosphodiesterase. WO PatentApplication No. 92/12961 does not disclose or suggest that thesecompound inhibit TNF. WO Patent Application No. 92/12961 also does notdisclose compounds wherein R¹ is lower alkyl substituted by halo; or R²is alkyl substituted by halo, cycloalkyl or cycloalkenyl, alkenyl,cycloalkyl substituted by halo, methylene or alkyl, cycloalkenyl,cyclothioalkyl or cyclothioalkenyl; or R¹ or R² attached to the phenylthrough sulfur; or R³ is aryl or heteroaryl each of which is substitutedby aralkoxy, aralkylthio, carboxy, aralkyloxycarbonyl, Y¹ Y² N--, Y¹ Y²NCO-- or Y¹ Y² NSO₂ -- where Y¹ and Y² are independently hydrogen,alkyl, aryl or aralkyl provided that one or both of Y¹ and Y² is aryl oraralkyl.

SUMMARY OF THE INVENTION

This invention is directed to the pharmaceutical use of a compound offormula I below to inhibit the production or physiological effects ofTNF in the treatment of a patient suffering from a disease stateassociated with a physiologically detrimental excess of tumor necrosisfactor (TNF), where formula I is as follows: ##STR10## wherein R¹ islower alkyl;

R² is alkyl, alkenyl, cycloalkyl, cycloalkenyl, cyclothioalkyl orcyclothioalken

R³ is aryl or heteroaryl;

Z, Z¹ and Z² are independently oxygen or sulfur;

Z³ is --CH═CH--, --C₋₋ C--, --CH₂ --CZ--, --CZCH₂ --, --CZ--CZ--, --CH₂--NH--, --CH₂ --O--, --CH₂ --S--, --CX₂ --O--, --CZNH--, --NH--CH₂ --,--O--CH₂ --, --SCH₂ --, --SOCH₂ --, --SO₂ CH₂ --, --O--CX₂ --,--O--CZ--, --NH--CZ--, --N═N--, --NH--SO₂ --, --SO₂ --NH--,--CZ--CZ--NH--, --NH--CO--O--, --O--CO--NH-- or --NH--CO--NH--; and

X is halo;

or an N-oxide thereof or a pharmaceutically acceptable salt thereof.

Compounds within the scope of the present invention also inhibit cyclicAMP phosphodiesterase, and are useful in treating a disease stateassociated with pathological conditions that are modulated by inhibitingcyclic AMP phosphodiesterase, such disease states including inflammatoryand autoimmune diseases, in particular type IV cyclic AMPphosphodiesterase.

DETAILED DESCRIPTION OF THE INVENTION

As used above, and throughout the description of the invention, thefollowing terms, unless otherwise indicated, shall be understood to havethe following meanings:

Definitions

"Patient" includes both human and other mammals.

"Alkyl" means an aliphatic hydrocarbon group which may be straight orbranched having about 1 to about 15 carbon atoms in the chain. Preferredalkyl groups have 1 to about 12 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl are attached to a linear alkyl chain. "Lower alkyl" means about 1to about 4 carbon atoms in the chain which may be straight or branched.The alkyl group may be substituted by one or more halo, cycloalkyl orcycloalkenyl. Exemplary alkyl groups include methyl, fluoromethyl,difluoromethyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl,ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, 3-pentyl, heptyl,octyl, nonyl, decyl and dodecyl.

"Alkenyl" means an aliphatic hydrocarbon group containing acarbon-carbon double bond and which may be straight or branched havingabout 2 to about 15 carbon atoms in the chain. Preferred alkenyl groupshave 2 to about 12 carbon atoms in the chain; and more preferably about2 to about 4 carbon atoms in the chain. Branched means that one or morelower alkyl groups such as methyl, ethyl or propyl are attached to alinear alkenyl chain. "Lower alkenyl" means about 2 to about 4 carbonatoms in the chain which may be straight or branched. The alkenyl groupmay be substituted by one or more halo. Exemplary alkenyl groups includeethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl,heptenyl, octenyl and decenyl.

"Cycloalkyl" means a non-aromatic mono- or multicyclic ring system ofabout 3 to about 10 carbon atoms. Preferred monocyclic cycloalkyl ringsinclude cyclopentyl, fluorocyclopentyl, cyclohexyl and cycloheptyl; morepreferred is cyclopentyl. The cycloalkyl group may be substituted by oneor more halo, methylene (H₂ C═) or alkyl. Exemplary multicycliccycloalkyl rings include 1-decalin, adamant-(1- or 2-)yl and norbornyl.

"Cycloalkenyl" means a non-aromatic monocyclic or multicyclic ringsystem containing a carbon-carbon double bond and having about 3 toabout 10 carbon atoms. Preferred monocyclic cycloalkenyl rings includecyclopentenyl, cyclohexenyl or cycloheptenyl; more preferred iscyclopentenyl. A preferred multicyclic cycloalkenyl ring isnorbornylenyl. The cycloalkenyl group may be substituted by one or morehalo, methylene (H₂ C═) or alkyl.

"Cyclothioalkyl" means a non-aromatic monocyclic or multicyclic ringsystem of about 3 to about 10 ring atoms. Preferred rings include about5 to about 6 ring atoms wherein one of the ring atoms is sulfur. Thecyclothioalkyl may be optionally substituted by one or more halo.Preferred monocyclic cyclothioalkyl rings include tetrahydrothiophenyland tetrahydrothiopyranyl; more preferred is tetrahydrothiophenyl. Thethio moiety of the cyclothioalkyl may also be optionally oxidized to thecorresponding S-oxide or S,S-dioxide.

"Cyclothioalkenyl" means a non-aromatic monocyclic or multicyclic ringsystem containing a carbon-carbon double bond and having about 3 toabout 10 ring atoms. Preferred rings include about 5 to about 6 ringatoms and wherein one of the ring atoms is sulfur. The cyclothioalkenylmay be optionally substituted by one or more halo. Preferred monocycliccyclothioalkyl rings include dihydrothiophenyl and dihydrothiopyranyl;more preferred is dihydrothiophenyl. The thio moiety of thecyclothioalkyl may also be optionally oxidized to the correspondingS-oxide or S,S-dioxide

"Aryl" means aromatic carbocyclic radical containing about 6 to about 10carbon atoms. Exemplary aryl include phenyl or naphthyl, or phenyl ornaphthyl substituted with one or more aryl group substituents which maybe the same or different, where "aryl group substituent" includeshydrogen, alkyl, aryl, aralkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy,aralkoxy, carboxy, acyl, aroyl, halo, nitro, cyano, carboxy,alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino,aroylamino, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl,alkylthio, arylthio, aralkylthio, Y¹ Y² N--, Y¹ Y² NCO-- or Y¹ Y² NSO₂--, where Y¹ and Y² are independently hydrogen, alkyl, aryl, andaralkyl. Preferred aryl group substituents include hydrogen, alkyl,hydroxy, acyl, aroyl, halo, nitro, cyano, alkoxycarbonyl, acylamino,alkylthio, Y¹ Y² N--, Y¹ Y² NCO-- or Y¹ Y² NSO₂ --, where Y¹ and Y² areindependently hydrogen and alkyl.

"Heteroaryl" means about a 5- to about a 10-membered aromatic monocyclicor multicyclic hydrocarbon ring system in which one or more of thecarbon atoms in the ring system is/are element(s) other than carbon, forexample nitrogen, oxygen or sulfur. The "heteroaryl" may also besubstituted by one or more aryl group substituents. Exemplary heteroarylgroups include pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl,isoxazolyl, isothiazolyl, quinolinyl, and isoquinolinyl. Preferredheteroaryl groups include pyrazinyl, thienyl, pyridyl, pyrimidinyl,isoxazolyl and isothiazolyl.

"Aralkyl" means an aryl-alkyl-group in which the aryl and alkyl are aspreviously described. Preferred aralkyls contain a lower alkyl moiety.Exemplary aralkyl groups include benzyl, 2-phenethyl andnaphthlenemethyl.

"Hydroxyalkyl" means a HO-alkyl-group in which alkyl is as previouslydefined. Preferred hydroxyalkyls contain lower alkyl. Exemplaryhydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.

"Acyl" means an H--CO-- or alkyl-CO-- group in which the alkyl group isas previously described. Preferred acyls contain a lower alkyl.Exemplary acyl groups include formyl, acetyl, propanoyl,2-methylpropanoyl, butanoyl and palmitoyl.

"Aroyl" means an aryl-CO-- group in which the alkyl group is aspreviously described. Exemplary groups include benzoyl and 1- and2-naphthoyl.

"Alkoxy" means an alkyl-O-- group in which the aryl group is aspreviously described. Exemplary alkoxy groups include methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy and beptoxy.

"Aryloxy" means an aryl-O-- group in which the aryl group is aspreviously described. Exemplary aryloxy groups include phenoxy andnaphthoxy.

"Aralkyloxy" means an aralkyl-O-- group in which the aralkyl groups isas previously described. Exemplary aralkyloxy groups include benzyloxyand 1- or 2-naphthalenemethoxy.

"Alkylthio" means an alkyl-S-- group in which the alkyl group is aspreviously described. Exemplary alkylthio groups include methylthio,ethylthio, i-propylthio and heptylthio.

"Arylthio" means an aryl-S-- group in which the aryl group is aspreviously described. Exemplary arylthio groups include phenylthio andnaphthylthio.

"Aralkylthio" means an aralkyl-S-- group in which the aralkyl group isas previously described. An exemplary aralkylthio group is benzylthio.

"Y¹ Y² N--" means a substituted or unsubstituted amino group, wherein Y¹and Y² are as previously described. Exemplary groups include amino (H₂N--), methylamino, ethylmethylamino, dimethylamino and diethylamino.

"Alkoxycarbonyl" means an alkyl-O--CO-- group. Exemplary alkoxycarbonylgroups include methoxy- and ethoxycarbonyl.

"Aryloxycarbonyl" means an aryl-O--CO-- group. Exemplary aryloxycarbonylgroups include phenoxy- and naphthoxycarbonyl.

"Aralkoxycarbonyl" means an aralkyl-O--CO-- group. An exemplaryaralkoxycarbonyl group is benzyloxycarbonyl.

"Y¹ Y² NCO--" means a substituted or unsubstituted carbamoyl group,wherein Y¹ and Y² are as previously described. Exemplary groups arecarbamoyl (H₂ NCO--) and dimethylcarbamoyl (Me₂ NCO--).

"Y¹ Y² NSO₂ --" means a substituted or unsubstituted sulfamoyl group,wherein Y¹ and Y² are as previously described. Exemplary groups aresulfamoyl (H₂ NSO₂ --) and dimethylsulfamoyl (Me₂ NSO₂ --).

"Acylamino" is an acyl-NH-- group wherein acyl is as defined herein.

"Aroylamino" is an aroyl-NH-- group wherein aroyl is as defined herein.

"Alkylsulfonyl" means an alkyl-SO₂ -- group. Preferred groups are thosein which the alkyl group is lower alkyl.

"Alkylsulfinyl" means an alkyl-SO-- group. Preferred groups are those inwhich the alkyl group is lower alkyl.

"Arylsulfonyl" means an aryl-SO₂ -- group.

"Arylsulfinyl" means an aryl-SO-- group.

"Halo" means fluoro, chloro, bromo, or iodo. Preferred are fluoro,chloro or bromo, and more preferred are fluoro or chloro.

Preferred Embodiments

A compound of formula I is preferred for use in treating a disease stateassociated with a physiologically detrimental excess of tumor necrosisfactor.

Disease states associated with pathological conditions that aremodulated by inhibiting cyclic AMP phosphodiesterase are also preferablytreated with a compound of formula I.

According to the compound aspect of the invention, preferred compoundsare described by formula I, provided that

when R¹ is methyl, R² is cyclopentyl, Z¹ and Z² are oxygen and R³ isphenyl, then Z³ is other than --COCH₂ --.

More preferred compounds of the present invention include those whereinR² is norbornyl, norbornenyl, cyclopentyl and cyclopentenyl; preferablycyclopentyl, norbomyl and norbornenyl.

According to a further aspect of the invention, more preferred compoundsof formula I are described wherein Z¹ and Z² are oxygen, or Z¹ is sulfurand Z² is oxygen are preferred. More preferred are where Z¹ and Z² areoxygen.

Compounds of the invention wherein R¹ is substituted by halo, preferablyfluoro, are also preferred. It is further preferred that the halosubstitution is on positions of the R¹ that are adjacent to the positionof R¹ that is attached respectively to Z¹.

Among the compounds of the invention where R³ is substituted phenyl, thephenyl group is preferably substituted on the 2-position or on both the2- and 6-positions.

Similarly, among compounds of the invention where R³ is substitutedheteroaryl, the heteroaryl group is preferably substituted on one orboth, more preferably on both, of the positions adjacent to the positionof R³ that is attached to Z³. Further preferred are compounds wherein R³is a 3,5-dihalopyrid-4-yl moiety or an N-oxide thereof.

Special embodiments of the compounds of the invention include those offormula I wherein Z³ is --CZNH--; and R¹ is lower alkyl optionallysubstituted by halo.

Special embodiments of the compounds also include those of formula Iwherein Z³ is --CZNH--; and R² is alkenyl, alkyl optionally substitutedby halo, cycloalkyl or cycloalkenyl, cyclothioalkyl, cyclothioalkenyl,cycloalkenyl optionally substituted by halo, methylene or alkyl orcycloalkyl optionally substituted by halo, methylene or alkyl. Furtherpreferred are compounds including those of formula I wherein Z³ is--CZNH--; and R² is cyclothioalkyl, cycloalkenyl optionally substitutedby halo or methylene, cycloalkyl optionally substituted by halo, oralkyl optionally substituted halo.

Special embodiments of the compounds also include those of formula Iwherein Z³ is --CZCH₂ --; and R² is alkenyl, alkyl optionallysubstituted by halo, cycloalkyl or cycloalkenyl, cyclothioalkyl,cyclothioalkenyl, cycloalkenyl optionally substituted by halo, methyleneor alkyl or cycloalkyl optionally substituted by halo, methylene oralkyl. Further preferred are compounds including those of formula Iwherein Z³ is --CZCH₂ --; and R² is cycloalkenyl, cycloalkyl optionallysubstituted by halo, or alkyl optionally substituted halo.

Another special embodiment of the compounds of the present inventioninclude those wherein Z³ is --CZNH--; and R³ is aryl or heteroaryl eachof which is substituted by aralkoxy, aralkylthio, carboxy,aralkyloxy-carbonyl, Y¹ Y² N--, Y¹ Y² NCO-- or Y¹ Y² NSO₂ -- where Y¹and Y² are independently hydrogen, alkyl, aryl or aralkyl, provided thatone or both of Y¹ and Y² is aryl or aralkyl.

Another special embodiment of the compounds of the present inventioninclude those wherein Z³ is --CZNH--; and Z¹ and Z² are oxygen or sulfurand at least one of Z¹ and Z² is sulfur; more preferred only one of Z¹and Z² is sulfur; and further preferred Z¹ is sulfur and Z² is oxygen.

A compound of formula I wherein Z³ is is --CH═CH--, --C₋₋ C--, --CH₂--CZ--, --CZ--CZ--, --CH₂ --NH--, --CH₂ --O--, --CH₂ --S--, --CX₂ --O--,--NH--CH₂ --, --O--CH₂ --, --SCH₂ --, --SOCH₂ --, --SO₂ CH₂ --, --O--CX₂--, --O--CZ--, --NH--CZ--, --N═N--, --NH--SO₂ --, --SO₂ --NH--,--CZ--CZ--NH--, --NH--CO--O--, --O--CO--NH-- or --NH--CO--NH-- isanother special embodiment of the compounds of the present invention.More preferred are compounds wherein Z³ is --O--CH₂ --, --O--CZ--,--NH--CZ--, --NH--CO--NH--, --CH₂ --NH--, --CH═CH--, --SO₂ --NH--,--N═N-- or --CZ--CZ--.

Preferred compounds for use according to the invention are selected fromthe following:

A N-(2,6-difluorophenyl)-3-cyclopentyloxy-4-methoxybenzamide;

B N-(2-chloro-6-fluorophenyl)-3-cyclopentyloxy-4-methoxybenzamide;

C N-(2-trifluoromethylphenyl)-3-cyclopentyloxy-4-methoxybenzamide;

D N-(2,4,6-trichlorophenyl)-3-cyclopentyloxy-4-methoxybenzamide;

E N-(2,6-dibromophenyl)-3-cyclopentyloxy-4-methoxybenzamide;

F N-(2-chloro-6-methylphenyl)-3-cyclopentyloxy-4-methoxybenzamide;

G N-(2,6-dichlorophenyl)-3-cyclopentyloxy-4-methoxybenzamide;

H N-(2-fluorophenyl)-3-cyclopentyloxy-4-methoxybenzamide;

I N-phenyl-3-cyclopentyloxy-4-methoxybenzamide;

J N-(2-methoxyphenyl)-3-cyclopentyloxy-4-methoxybenzamide;

K N-(2-chlorophenyl)-3-cyclopentyloxy-4-methoxybenzamide;

L N-(3-chlorophenyl)-3-cyclopentyloxy-4-methoxybenzamide;

M N-(4-methoxyphenyl)-3-cyclopentyloxy-4-methoxybenzamide;

N N-(2,6-dimethylphenyl)-3-cyclopentyloxy-4-methoxybenzamide;

O N-(2-methylthiophenyl)-3-cyclopentyloxy-4-methoxybenzamide;

P N-(2-bromophenyl)-3-cyclopentyloxy-4-methoxybenzamide;

Q N-(2-methoxycarbonylphenyl)-3-cyclopentyloxy-4-methoxybenzamide;

R N-(2-aminosulfonylphenyl)-3-cyclopentyloxy-4-methoxybenzamide;

S N-(2-benzoylphenyl)-3-cyclopentyloxy-4-methoxybenzamide;

T N-(2-cyanophenyl)-3-cyclopentyloxy-4-methoxybenzamide;

U N-(2,5-dichlorophenyl)-3-cyclopentyloxy-4-methoxybenzamide;

V N-(3-methylphenyl)-3-cyclopentyloxy-4-methoxybenzamide;

W N-(2-nitrophenyl)-3-cyclopentyloxy-4-methoxybenzamide;

X N-(2-dimethylaminophenyl)-3-cyclopentyloxy-4-methoxybenzamide;

Y N-(2-acetylphenyl)-3-cyclopentyloxy-4-methoxybenzamide;

Z N-(2-hydroxyphenyl)-3-cyclopentyloxy-4-methoxybenzamide;

AA N-(2-methylsulfonylphenyl)-3-cyclopentyloxy-4-methoxybenzamide;

AB N-(2,6-difluorophenyl)-3-cyclohexyloxy-4-methoxybenzamide;

AC N-(2,6-difluorophenyl)-3-butoxy-4-methoxybenzamide;

AD N-(2,6-difluorophenyl)-3-propoxy-4-methoxybenzamide;

AE N-(2-chlorophenyl)-3-cyclopentyloxy-4-methoxy(thiobenzamide);

AF N-(4-chloropyrid-3-yl)-3-cyclopentyloxy-4-methoxybenzamide;

AG N-pyrid-2-yl-3-cyclopentyloxy-4-methoxybenzamide;

AH N-pyrazin-2-yl-3-cyclopentyloxy-4-methoxybenzamide;

AI N-pyrimidin-2-yl-3-cyclopentyloxy-4-methoxybenzamide;

AJ N-(3-methylpyrid-2-yl)-3-cyclopentyloxy-4-methoxybenzamide;

AK N-pyrid-3-yl-3-cyclopentyloxy-4-methoxybenzamide;

AL N-(3-chloropyrid-2-yl)-3-cyclopentyloxy-4-methoxybenzamide;

AM N-(3-chloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide;

AN N-pyrid-4-yl-3-cyclopentyloxy-4-methoxybenzamide;

AO N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide;

AP N-(3,5-dimethylisoxazol-4-yl)-3-cyclopentyloxy-4-methoxybenzamide;

AQ N-(4,6-dichloropyrimid-5-yl)-3-cyclopentyloxy-4-methoxybenzamide;

AR N-(4-nitrophenyl)-3-cyclopentyloxy-4-methoxybenzamide;

ASN-(2,3,5,6-tetrafluoropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide;

ATN-(3,5-dichloro-2,6-difluoropyrid-4-yl)-3-cyclopentyloxy-4-methoxy-benzamide;

AU N-(2,4,6-trifluorophenyl)-3-cyclopentyloxy-4-methoxybenzamide;

AV 3,5-dichloro-4-(3-cyclopentyloxy-4-methoxybenzamido)pyridine-N-oxide;

AWN-(3,5-dichloropyrid-4-yl)-3-(exo-8,9,10-trinorbornyl-2-oxy)-4-methoxy-benzamide;

AX N-(3,5-dichloropyrid-4-yl)-3-cyclohexyloxy-4-methoxybenzamide;

AY N-(3,5-dibromopyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide,

AZ N-(3,5-dichloropyrid-4-yl)-3-butoxy-4-methoxybenzamide;

BAN-(3-methyl-5-bromoisothiazol-4-yl)-3-cyclopentyloxy-4-methoxy-benzamide;

BB N-(3,5-dimethylisothiazol-4-yl)-3-cyclopentyloxy-4-methoxybenzamide;

BC N-(3,5-dimethylpyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide;

BDN-(5-cyano-3-methylisothiazol-4-yl)-3-cyclopentyloxy-4-methoxy-benzamide;

BE N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxy(thiobenzamide);

BFN-(2,6-dichloro-4-methoxyphenyl)-3-cyclopentyloxy-4-methoxy-benzamide;

BG N-(2,6-dichloro-4-cyanophenyl)-3-cyclopentyloxy-4-methoxybenzamide;

BHN-(2,6-dichloro-4-carbamoylphenyl)-3-cyclopentyloxy-4-methoxy-benzamide;

BI N-(2,6-dichloro-4-aminophenyl)-3-cyclopentyloxy-4-methoxy-benzamide;

BJN-(3-chloro-2,5,6-trifluoropyrid-4-yl)-3-cyclopentyloxy-4-methoxy-benzamide;

BK N-(3,5-dibromopyrid-4-yl)-3-butoxy-4-methoxy-benzamide;

BLN-(2,6-dichloro-4-methoxycarbonylphenyl)-3-cyclopentyloxy-4-methoxy-benzamide;

BMN-(4-acetylamino-2,6-dichlorophenyl)-3-cyclopentyloxy-4-methoxy-benzamide;

BN N-(3,5-dichloropyrid-4-yl)-3-nonyloxy-4-methoxybenzamide;

BO N-(2,6-dichloro-4-formylphenyl)-3-cyclopentyloxy-4-methoxybenzamide;

BPN-(2,6-dichlorophenyl)-3-(exo-8,9,10-trinorbornyl-2-oxy)-4-methoxy-benzamide;

BQ N-(2,3,5-trifluoropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide;

BR sodium salt ofN-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxy-benzamide;

BSN-(2,6-dichloro-4-ethoxycarbonylphenyl)-3-cyclopentyloxy-4-methoxy-benzamide;

BTN-(2,6-dichloro-4-hydroxymethylphenyl)-3-cyclopentyloxy-4-methoxy-benzamide;

BU N-(3,5-dichloropyrid-4-yl)-3-dodecyloxy-4-methoxybenzamide;

BV(R)-N-(3,5-dichloropyrid-4-yl)-3-(exo-8,9,10-trinorbornyl-2-oxy)-4-methoxybenzamide;

BW(S)-N-(3,5-dichloropyrid-4-yl)-3-(exo-8,9,10-trinorbornyl-2-oxy)-4-methoxybenzamide;

BX N-(2,6-dichloro-4-nitrophenyl)-3-cyclopentyloxy-4-methoxybenzamide;

BY N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-(methylthio)benzamide;

BZ N-(3,5-difluoropyrid-4-yl)-3-cyclopentyloxy-4-(methylthio)benzamide;

CAN-(3,5-dichloropyrid-4-yl)-3-(exo)-8,9,10-trinorbornyl-2-oxy-4-(methylthio)benzamide;

CB(R)-N-(3,5-dichloropyrid-4-yl)-3-(exo)-8,9,10-trinorbornyl-2-oxy-4-(methylthio)benzamide;

CC(S)-N-(3,5-dichloropyrid-4-yl)-3-(exo)-8,9,10-trinorbornyl-2-oxy-4-(methylthio)benzamide;

CD(±)-N-(3,5-dichloropyrid-4-yl)-3-cyclopent-2-enyloxy-4-methoxy-benzamide;

CFN-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-difluoromethoxy-benzamide;

CG 3-cyclopentylthio-N-(3,5-dichloropyrid-4-yl)-4-methoxybenzamide;

CH N-(3,5-dichloropyrid-4-yl)-3-isopropylthio-4-methoxybenzamide;

CIN-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-(fluoromethylthio)-benzamide;

CJ 3-cyclopentyloxy-4-methoxyphenyl 2',6'-dichlorobenzyl ketone;

CK 3-cyclopentyloxy-4-methoxyphenyl 3,5-dichloropyrid-4-ylmethyl ketone;

CL3,5-dichloro-4-(2-(3-cyclopentyloxy-4-methoxyphenyl)-2-oxoethyl)-pyridine-N-oxide;

CM 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(3-chloropyrid-4-yl)ethanone;

CN 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethanone;

CO 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethanone;

CP3-(3-methyl-2-butenyloxy)-N-(3,5-dichloropyrid-4-yl)-4-methoxy-benzamide;

CQN-(3,5-dichloropyrid-4-yl)-3-[exobicyclo(2.2.1)hept-5-en-2-yloxy]-4-methoxybenzamide;

CR N-(3-cyclopentyloxy-4-methoxyphenyl)-2,6-dichlorobenzamide;

CS N-(3-cyclopentyloxy-4-methoxyphenyl)-2,6-difluorobenzamide;

CT N-(2,6-dichlorophenyl)-N'-(3-cyclopentyloxy-4-methoxyphenyl)urea;

CU N-(3,5-dichloropyrid-4-yl)-N'-(3-cyclopentyloxy-4-methoxyphenyl)urea;

CV (3-cyclopentyloxy-4-methoxyphenyl)-2,6-dichlorobenzoate;

CW 3-cyclopentyloxy-4-methoxyphenyl-2,6-dichlorobenzyl ether;

CX N-(2-chlorophenyl)-3-cyclopentyloxy-4-methoxybenzylamine;

CY 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(2,6-dichlorophenyl)ethene;

CZ 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(2,6-difluorophenyl)ethene;

DA 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(pyrid-4-yl)ethane-1,2-dione;

DBtrans-1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(3,5-dichloropyrid-4-yl)-diazene;

DC1-(3-cyclopentyloxy-4-methoxyphenyl)-c-1-oxo-r-2-(3,5-dichloro-1-oxo-pyrid-4-yl)diazene,

DDtrans-1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(3,5-dichloro-1-oxo-pyrid-4-yl)diazene;

DE N-(2-chlorophenyl)-3-cyclopentyloxy-4-methoxybenzenesulfonamide;

DF 3-cyclopentyloxy-N-(3,5-difluoropyrid-4-yl)-4-methoxybenzamide;

DG(R)-N-(2,6-dichlorophenyl)-3-(exo-8,9,10-trinorbornyl-2-oxy)-4-methoxy-benzamide;

DH(S)-N-(2,6-dichlorophenyl)-3-(exo-8,9,10-trinorbornyl-2-oxy)-4-methoxy-benzamide;

DI 3-cyclopentylmethoxy-N-(3,5-dichloropyrid-4-yl)-4-methoxybenzamide;

DJ 3-cyclopropylmethoxy-N-(3,5-dichloropyrid-4-yl)-4-methoxybenzamide;

DK N-(3-bromo-5-chloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide;

DL N-(3,5-dichloropyrid-4-yl)-3-isopropoxy-4-methoxybenzamide;

DM 3-tert-butoxy-N-(3,5-dichloropyrid-4-yl)-4-methoxybenzamide;

DN N-(3,5-dichloropyrid-4-yl)-4-methoxy-3-(pent-3-yloxy)benzamide;

DON-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-trifluoromethoxy-benzamide;

DPN-(3,5-dichloropyrid-4-yl)-3-(4,4-difluoro-3-methylenecyclobut-1-enyloxy)-4-methoxybenzamide;

DQ N-(3,5-difluoropyrid-4-yl)-3-isopropoxy-4-difluoromethoxybenzamide;

DRN-(3,5-difluoro-1-oxido-4-pyridinio)-3-isopropoxy-4-difluoromethoxy-benzamide;

DS N-(3,5-dichloro-pyrid-4-yl)-3-isopropoxy-4-difluoromethoxybenzamide;

DTN-(3,5-dichloro-1-oxido-4-pyridinio)-3-isopropoxy-4-difluoromethoxy-benzamide;

DUN-(3,5-dichloro-4-pyridyl)-4-difluoromethoxy-3-(exo)-8,9,10-trinorborn-2-yloxybenzamide;

DVN-(3,5-dichloro-1-oxido-4-pyridinio)-4-difluoromethoxy-3-(exo)-8,9,10-trinorborn-2-yloxybenzamide;

DWN-(3,5-dichloropyrid-4-yl)-3-(2-fluorocyclopentyloxy)-4-methoxy-benzamide;

DXN-(3,5-dichloro-pyrid-4-yl)-3-(tetrahydrothiophen-3-oxy)-4-methoxy-benzamide;

DY3-cyclopentyloxy-N-(3,5-dichloro-1-oxido-4-pyridinio)-4-difluoromethoxybenzamide;

DZ N-(3,5-dichloropyrid-4-yl)-3-isopropoxy-4-(methylthio)benzamide;

EA N-(3,5-difluoropyrid-4-yl)-3-isopropoxy-4-(methylthio)benzamide;

EB N-(3,5-dichloropyrid-4-yl)-3-(pent-3-yloxy)-4-(methylthio)benzamide;

EC(±)-1-[3-{(exo)-8,9,10-trinorbornyl-2-oxy}-4-methoxyphenyl]-2-(3,5-dichloropyrid-4-yl)ethanone;

ED1-[3-cyclopentyloxy-4-(methylthio)phenyl]-2-(3,5-dichloropyrid-4-yl)-ethanone;

EE 1(4-methoxy-3-prop-2-yloxyphenyl)-2-(3,5-dichloropyrid-4-yl)ethanone;

EF1-(4-methylthio-3-prop-2-yloxyphenyl)-2-(3,5-dichloropyrid-4-yl)-ethanone;

EG1-(4-methoxy-3-prop-2-yloxyphenyl)-2-(3,5-dichloro-1-oxido-4-pyridinio)ethanone;

EH1-(3-cyclopentyloxy-4-difluoromethoxyphenyl)-2-(3,5-dichloropyrid-4-yl)ethanone;

EI1-(3-cyclopentyloxy-4-difluoromethoxyphenyl)-2-(3,5-dichloro-1-oxido-4-pyridinio)ethanone;

EJ2-(3,5-dichloropyrid-4-yl)-1-[3-{exobicyclo(2.2.1)hept-5-en-2-yloxy}-4-methoxyphenyl]ethanone;

EK2-(3,5-dichloro-4-pyridyl)-1-(4-difluoromethoxy-3-(exo)-8,9,10-trinorborn-2-yloxyphenyl)ethanone;

EL2-(3,5-dichloro-1-oxido-4-pyridinio)-1-[4-difluoromethoxy-3-(exo)-8,9,10-trinorborn-2-yloxyphenyl]ethanone;

EM2-(3,5-dichloro-4-pyridyl)-1-[4-methoxy-3-(3-methyl-2-butenyloxy)-phenyl]ethanone;

EN2-(3,5-dichloro-4-pyridyl)-1-(4-difluoromethoxy-3-isopropoxyphenyl)-ethanone;

EO2-(3,5-dichloro-1-oxido-4-pyridinio)-1-(4-difluoromethoxy-3-isopropoxyphenyl)ethanone;

EP 3,5-dichloro-4-(3-cyclopentyloxy-4-metboxyphenoxymethyl)pyridine; and

EQN-(3,5-dichloro-1-oxido-4-pyridinio-4-methoxy-3-(exo)-8,9,10-trinorborn-2-yloxy-benzamide.

Preferred compounds include AO, AV, AW, BV, BW, BY, CF, CK, CL, CQ, DU,EC, EJ, EK, EL and EQ.

The letters A to EQ are allocated to compounds for easy reference inthis specification.

Compounds of formula I may be prepared by the application or adaptationof known methods, by which is meant methods used heretofore or describedin the literature.

Thus, compounds of formula I ##STR11## wherein R¹, R², R³, Z¹ and Z²,are as hereinbefore defined, Z³ represents a --CZNH-- linkage, and Zrepresents oxygen, may be prepared by the reaction of compounds offormula II ##STR12## hereinafter depicted, wherein R¹, R², Z¹ and Z² areas hereinbefore defined and X represents halo, e.g. bromo or,preferably, chloro, with compounds of the formula III

    R.sup.3 NH.sub.2                                           III

wherein R³ is as hereinbefore defined, preferably in the presence of abase such as an alkali metal hydride, e.g. sodium hydride, or an amine,preferably a tertiary amine, e.g. triethylamine or pyridine, optionallyin an inert solvent, for example dichloromethane, dimethylformamide, oran ether, e.g. diethyl ether or tetrahydrofuran, preferably at atemperature from 0° C. to the reflux temperature or at the melting pointof the reaction mixture.

Alternatively, compounds of formula I, wherein R¹, R² and R³, are ashereinbefore defined, Z, Z¹ and Z² are oxygen, and Z³ represents a--CZNH-- linkage, may be prepared by the reaction of compounds offormula I' ##STR13## hereinafter depicted, wherein R¹ and R² are ashereinbefore defined, R^(3') is hydrogen, Z, Z¹ and Z² are oxygen and Z³represents a --CZNH-- linkage, with compounds of the formula V'

    R.sup.3 X                                                  V'

wherein R³ and X are as hereinbefore defined, preferably X is chloro,and preferably the preparation takes place in the presence of a base,for example an alkali metal hydride, e.g. sodium hydride, an alkalimetal alkoxide, e.g. potassium t-butoxide, an alkali metal hydroxide,e.g. sodium hydroxide or carbonate, or an amine, preferably a tertiaryamine, e.g. triethylamine or pyridine, optionally in an inert solvent,for example dichloromethane, dimethylformamide, or an ether, e.g.diethyl ether or tetrahydrofuran, preferably at a temperature from 0° C.to the reflux temperature.

Alternatively, compounds of formula I, wherein R¹, R², R³, Z, Z¹ and Z²,are as hereinbefore defined, Z³ represents a --CZNH-- linkage, may beprepared by the reaction of compounds of formula IV ##STR14##hereinafter depicted, wherein R¹, R³, Z, Z¹ and Z² are as hereinbeforedefined and Z³ represents a --CZNH-- linkage, with compounds of theformula V

    R.sup.2 X                                                  V

wherein R² is as hereinbefore defined, preferably, X is as hereinbeforedefined or p-toluenesulfonate, preferably X is bromo, and preferably thepreparation takes place in the presence of a base, for example an alkalimetal hydride, e.g. sodium hydride, an alkali metal hydroxide orcarbonate, e.g. sodium hydroxide or carbonate, or an amine, preferably atertiary amine, e.g. triethylamine or pyridine, optionally in an inertsolvent, for example dichloromethane, dimethylformamide, or an ether,e.g. diethyl ether or tetrahydrofuran, preferably at a temperature from0° C. to the reflux temperature.

Alternatively, compounds of formula I, wherein R¹, R², R³, Z¹ and Z²,are as hereinbefore defined, Z³ represents a --CZCH₂ -- linkage, and Zrepresents oxygen, are prepared from compounds of formula VI ##STR15##wherein R¹, R², R³, Z¹ and Z² are as hereinbefore defined, by oxidationby the application or adaptation of known methods. The oxidation iscarried out, for example, by reaction with oxalyl chloride and dimethylsulfoxide, in a solvent such as dichloromethane, and preferably at atemperature lower than -65° C. Alternatively, the oxidation is carriedout by reaction with chromium trioxide in the presence of3,5-dimethylpyrazole.

According to a further feature of the present invention, compounds offormula I, wherein R¹, R², R³, Z, Z¹ and Z², are as hereinbeforedefined, Z³ represents a --CZCH₂ -- linkage, and preferably thosewherein Z represents oxygen, are prepared from compounds of formula VII##STR16## wherein R¹, R², Z, Z¹ and Z² are as hereinbefore defined andR⁴ and R⁵ represent lower alkyl, e.g. methyl, groups, by coupling withcompounds of the formula VIII

    R.sup.3 CH.sub.3                                           VIII

wherein R³ is as hereinbefore defined, in the presence of a strong basesuch as lithium diisopropylamide (usually prepared in situ from butyllithium and diisopropylamine), preferably at a low temperature.

According to a feature of the present invention, compounds of formula I,wherein R¹, R², R³, Z¹ and Z², are as hereinbefore defined, Z³represents a --CZCH₂ linkage, and Z represents oxygen, are prepared bythe reaction of compounds of formula IX ##STR17## wherein R¹, R², Z¹ andZ² are as hereinbefore defined, with compounds of the formula X

    R.sup.3 MgX                                                X

wherein R³ and X are as hereinbefore defined.

Alternatively, compounds of formula I, wherein R¹, R², R³, Z¹ and Z² areas hereinbefore defined and Z³ represents an --O--CH2-- linkage areprepared by the reaction of compounds of the formula XI ##STR18##wherein R¹, R², Z¹ and Z² are as hereinbefore defined, with compounds ofthe formula XII

    R.sup.3 CH.sub.2 X.sup.2                                   XII

wherein R³ and X are as hereinbefore defined, and X is preferablychloro, preferably takes place in the presence of a base such as analkali metal carbonate, e.g. potassium carbonate, preferably in asolvent such as dimethylformamide.

According to a further feature of the present invention, compounds offormula I, wherein R¹, R², R³, Z¹ and Z² are as hereinbefore defined andZ³ represents an --O--CO-- linkage are prepared by the reaction ofcompounds of formula XI above, wherein R¹, R², Z¹ and Z² are ashereinbefore defined, with compounds of the formula XIII

    R.sup.3 COX                                                XIII

wherein R³ and X are as hereinbefore defined, and X is preferablychloro, preferably in the presence of a base such as a tertiary amine,e.g. triethylamine, preferably in a solvent such as dichloromethane.

According to a further feature of the present invention, compounds offormula I, wherein R¹, R², R³, Z¹ and Z² are as hereinbefore defined andZ³ represents an --NH--CO-- linkage are prepared by the reaction ofcompounds of formula XIV ##STR19## wherein R¹, R², Z¹ and Z² are ashereinbefore defined, with compounds of formula XIII above, wherein R³and X² are as hereinbefore defined, preferably in the presence of a basesuch as a tertiary amine, e.g. triethylamine, preferably in a solventsuch as dichloromethane.

According to a further feature of the present invention, compounds offormula I, wherein R¹, R², R³, Z¹ and Z² are as hereinbefore defined andZ³ represents an --NH--CO--NH-- linkage are prepared by the reaction ofcompounds of formula XIV above, wherein R¹, R², Z¹ and Z² are ashereinbefore defined, with compounds of the formula XV

    R.sup.3 NCO                                                XV

wherein R³ is as hereinbefore defined, preferably in the presence of abase such as a tertiary amine, e.g. triethylamine, preferably in asolvent such as dichloromethane.

According to a further feature of the present invention, compounds offormula I, wherein R¹, R², R³, Z¹ and Z² are as hereinbefore defined andZ³ represents an --NH--CO--NH-- linkage are prepared by the reaction ofcompounds of formula XIV, wherein R¹, R², Z¹ and Z² are as hereinbeforedefined, with compounds of the formula III above, wherein R³ is ashereinbefore defined, preferably by reacting the compound of formula XIVwith phosgene or, preferably, bis(trichloromethyl) carbonate, and bythen reacting the product of that reaction with the cation derived fromthe compound of formula III (for example by reaction with a base such assodium hydride). The reactions are preferably carried out in suitablesolvents such as dichloromethane and tetrahydrofuran.

According to a further feature of the present invention, compounds offormula I, wherein R¹, R², R³, Z¹ and Z² are as hereinbefore defined andZ³ represents a --CH₂ --NH-- linkage are prepared by the reaction ofcompounds of formula XVI ##STR20## wherein R¹, R², Z¹ and Z² are ashereinbefore defined, with compounds of formula III above, wherein R³ isas hereinbefore defined, followed by reduction with a compound such assodium cyanoborohydride. This process is especially suitable forcompounds wherein R³ represents an optionally substituted phenyl ornaphthyl group.

According to a further feature of the present invention, compounds offormula I, wherein R¹, R², R³, Z¹ and Z² are as hereinbefore defined andZ³ represents a --CH2--NH-- linkage are prepared by the reaction ofcompounds of formula XVII ##STR21## wherein X, R¹, R², Z¹ and Z² are ashereinbefore defined, and X is preferably bromo, with compounds offormula above, wherein R³ is as hereinbefore defined, preferably in thepresence of a base such as sodium hydride. This process is especiallysuitable for compounds wherein R³ represents an optionally substitutedheteroaryl group.

According to a further feature of the present invention, compounds offormula I, wherein R¹, R², R³, Z¹ and Z² are as hereinbefore defined andZ³ represents a trans --CH═CH-- linkage are prepared by the reaction ofcompounds of formula XVI above, wherein R¹, R², Z¹ and Z² are ashereinbefore defined, with the reaction product of a compound of theformula XVIII

    (R.sup.4 PCH.sub.2 R.sup.3).sup.+ (X).sup.-                XVIII

(wherein R³ is as hereinbefore defined, R⁴ represents an aryl e.g.phenyl group, and X represents halo, preferably bromo) with a base suchas an alkali metal alkoxide, e.g. potassium t-butoxide. The reaction ispreferably carried out in a solvent such as tetrahydrofuran.

According to a further feature of the present invention, compounds offormula I, wherein R¹, R², R³, Z¹ and Z² are as hereinbefore defined andZ³ represents an --SO₂ --NH-- linkage are prepared by the reaction ofcompounds of formula XIX ##STR22## wherein R¹, R³, Z¹ and Z² are ashereinbefore defined, with compounds of the formula V

    R.sup.2 X                                                  V

wherein R² and X are as hereinbefore defined, preferably after treatmentwith a base such as sodium hydride, preferably in a solvent such asdimethylformamide.

According to a further feature of the present invention, compounds offormula I, wherein R¹, R², R³, Z¹ and Z² are as hereinbefore defined andZ³ represents an --S--CH2-- linkage are prepared by the reaction ofcompounds of formula XX ##STR23## wherein R¹, R², Z¹ and Z² are ashereinbefore defined, with compounds of formula XII above, wherein R²and X are as hereinbefore defined, and preferably X is bromo, preferablyafter reaction with a base such as an alkali metal alkoxide, e.g. sodiummethoxide.

According to a further feature of the present invention, compounds offormula I, wherein R¹, R², R³, Z¹ and Z² are as hereinbefore defined andZ³ represents a --CF2--O-- linkage are prepared by the reaction ofcompounds of formula XXI ##STR24## wherein R¹, R², Z¹ and Z² are ashereinbefore defined, with compounds of the formula XXII

    R.sup.3 OH                                                 XXII

wherein R³ is as hereinbefore defined, preferably with the aid of a basesuch as sodium hydride, preferably in a solvent such as tetrahydrofuran.

According to a further feature of the present invention, compounds offormula I, wherein R¹, R², R³, Z¹ and Z² are as hereinbefore defined andZ³ represents an --NH--CO--O-- linkage are prepared by the reaction ofcompounds of formula XXIII ##STR25## wherein R¹, R², Z¹ and Z² are ashereinbefore defined, with compounds of formula XII above, wherein R³ isas hereinbefore defined, preferably with the aid of a base such as atertiary amine, e.g. triethylamine, preferably in a solvent such asdichloromethane.

According to a further feature of the present invention, compounds offormula I, wherein R¹, R², R³, Z¹ and Z² are as hereinbefore defined andZ³ represents an --NH--CH₂ -- linkage are prepared by the reaction ofcompounds of formula XIV above, wherein R¹, R², Z¹ and Z² are ashereinbefore defined, with compounds of the formula XXIV

    R.sup.3 CHO                                                XXIV

wherein R³ is as hereinbefore defined, preferably with the aid of areducing agent such as sodium cyanoborohydride.

According to a further feature of the present invention, compounds offormula I, wherein R¹, R², R³, Z¹ and Z² are as hereinbefore defined andZ³ represents an --NH--SO₂ -- linkage are prepared by the reaction ofcompounds of formula XIV above, wherein R¹, R², Z¹ and Z² are ashereinbefore defined, with compounds of the formula XXV

    R.sup.3 SO.sub.2 X                                         XXV

wherein R³ and X are as hereinbefore defined, preferably with the aid ofa base such as a tertiary amine, e.g. triethylamine, preferably in asolvent such as tetrahydrofuran.

According to a further feature of the present invention, compounds offormula I, wherein R¹, R², R³, Z¹ and Z² are as hereinbefore defined andZ³ represents an --O--CO--NH-- linkage are prepared by the reaction ofcompounds of formula XI above, wherein R¹, R², Z¹ and Z² are ashereinbefore defined, with compounds of formula XV above, wherein R³ isas hereinbefore defined, or with a compound of formula III above,wherein R³ is as hereinbefore defined, and phosgene or, preferably,bis(trichloromethyl) carbonate, preferably with the aid of a base suchas a tertiary amine, e.g. triethylamine, preferably in a solvent such asdichloromethane.

According to a further feature of the present invention, compounds offormula I, wherein R¹, R², R³, Z¹ and Z² are as hereinbefore defined andZ³ represents an --O--CF₂ -- linkage are prepared by the reaction ofcompounds of formula XI above, wherein R¹, R², Z¹ and Z² are ashereinbefore defined, with compounds of the formula XXV

    R.sup.3 CF.sub.2 Br                                        XXV

wherein R³ is as hereinbefore defined, preferably with the aid of a basesuch as sodium hydride, preferably in a solvent such as tetrahydrofuran.

According to a further feature of the present invention, compounds offormula I, wherein R¹, R², R³, Z¹ and Z² are as hereinbefore defined andZ³ represents an ethynyl linkage are prepared by the reaction ofcompounds of formula XXVI ##STR26## hereinafter depicted, wherein R¹,R², Z¹ and Z² are as hereinbefore defined, with compounds of the formulaXXVII

    R.sup.3 X.sup.1                                            XXVII

wherein R³ is as hereinbefore defined and X¹ represents an ethynylgroup. Preferably the reaction is carried out with the aid of acatalyst, e.g. palladium on carbon, and cuprous iodide, preferably withthe aid of a base such as a tertiary amine, e.g. triethylamine,preferably in a solvent such as dimethylformamide.

According to a further feature of the present invention, compounds offormula I, wherein R¹, R², R³, Z¹ and Z² are as hereinbefore defined andZ³ represents a --CH₂ --O-- linkage are prepared by the reaction ofcompounds of formula XXVIII ##STR27## wherein R¹, R², Z¹ and Z² are ashereinbefore defined, with compounds of the formula V above, wherein R³and X are as hereinbefore defined, preferably with the aid of a basesuch as an alkali metal alkoxide, e.g. potassium t-butoxide. Thereaction is preferably carried out in a solvent such as tetrahydrofuran.

According to a further feature of the present invention, compounds offormula I, wherein R¹, R², R³, Z¹ and Z² are as hereinbefore defined andZ³ represents a --CH₂ --O-- linkage are prepared by the reaction ofcompounds of formula XVII above, wherein R¹, R², Z¹, Z² and X are ashereinbefore defined, with compounds of formula XXII above, wherein R³is as hereinbefore defined, preferably with the aid of a base such as analkali metal alkoxide, e.g. potassium t-butoxide.

According to a further feature of the present invention, compounds offormula I, wherein R¹, R², R³, Z¹ and Z² are as hereinbefore defined andZ³ represents a --CO--CO--NH-- linkage are prepared by the reaction ofcompounds of formula XXIX ##STR28## wherein R¹, R², Z¹ and Z² are ashereinbefore defined, with dichloromethyl methyl ether indichloromethane, followed by reaction with compounds of formula IIIabove, wherein R³ is as hereinbefore defined, preferably with the aid ofa base such as sodium hydride, preferably in a solvent such astetrahydrofuran.

According to a further feature of the present invention, compounds offormula I, wherein R¹, R², R³, Z¹ and Z² are as hereinbefore defined andZ³ represents a --CO--CO-- linkage are prepared by the oxidation ofcompounds of formula VI above, wherein R¹, R², R³, Z¹ and Z² are ashereinbefore defined, for example by reaction with pyridiniumdichromate, preferably in a solvent such as dichloromethane. Thisreaction is particularly suitable for compounds wherein R³ represents aheteroaryl, preferably an optionally substituted pyridyl, group.

According to a further feature of the present invention, compounds offormula I, wherein R¹, R², R³, Z¹ and Z² are as hereinbefore defined andZ³ represents a trans --N═N-- linkage are prepared by the reaction ofcompounds of formula XXX ##STR29## wherein R¹, R², R³, Z¹ and Z² are ashereinbefore defined, with compounds of the formula XXXI

    R.sup.3 H                                                  XXXI

wherein R³ is as hereinbefore defined, preferably with the aid of a basesuch as lithium diisopropylamide.

According to a further feature of the present invention, compounds offormula I, wherein R¹, R², R³, Z¹ and Z² are as hereinbefore defined andZ represents a --CH₂ --S-- linkage are prepared by the reaction ofcompounds of formula XVII, wherein X, R¹, R², Z¹ and Z² are ashereinbefore defined, with compounds of the formula XXXIII

    R.sup.3 --SH                                               XXXIII

wherein R³ is as hereinbefore defined, preferably with the aid of a basesuch as an alkali metal carbonate, e.g. potassium carbonate.

According to a further feature of the present invention, compounds offormula I, wherein R¹, R², R³, Z¹ and Z² are as hereinbefore defined andZ³ represents a --CH₂ --CO-- linkage are prepared by the oxidation ofcompounds of formula XXXIV ##STR30## wherein R¹, R², R³, Z¹ and Z² areas hereinbefore defined. The oxidation is carried out, for example, byreaction with oxalyl chloride and dimethyl sulfoxide, in a solvent suchas dichloromethane, and preferably at a temperature lower than -65° C.Alternatively, the oxidation is carried out by reaction with chromiumtrioxide in the presence of 3,5-dimethylpyrazole.

As another example, compounds of formula I wherein R¹, R², R³, Z¹ and Z²are as hereinbefore defined, and Z³ represents a cis --C═C-- or cis--N═N-- linkage are prepared by the action of ultraviolet radiation upontheir trans-isomers.

As another example, compounds of formula I wherein R¹, R², R³, Z¹ and Z²are as hereinbefore defined, Z¹ and Z² preferably each represent oxygen,and Z³ represents an --SO--CH₂ -- linkage are prepared by the oxidationof corresponding compounds wherein Z³ represents an --S--CH₂ -- linkage.For example, the oxidation can be carried out by means of potassiumhydrogen peroxomonosulfate in a medium such as aqueous methanol.

As another example, compounds of formula I wherein R¹, R², R³, Z¹ and Z²are as hereinbefore defined, Z¹ and Z² preferably each represent oxygen,and Z³ represents an --SO₂ --CH₂ -- linkage are prepared by theoxidation of corresponding compounds wherein Z³ represents an --S--CH₂-- linkage. For example, the oxidation can be carried out by means ofsodium iodate in a medium such as aqueous methanol.

As another example, compounds of formula I wherein R¹, R², R³, Z¹ and Z²are as hereinbefore defined, Z³ represents a --CZCH₂ -- linkage, and Zrepresents sulfur are prepared from compounds of formula I wherein R¹,R², R³, Z¹ and Z² are as hereinbefore defined, Z³ represents a --CZCH₂-- linkage, and Z represents oxygen, by reaction with phosphoruspentasulfide or2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide,preferably in a solvent such as pyridine or toluene, and preferably at atemperature from 0° C. to the reflux temperature.

As another example, compounds of formula I wherein R¹, R², Z, Z¹, Z² andZ³ are as hereinbefore defined, Z, Z¹ and Z² preferably each representoxygen, and R³ is as hereinbefore defined and contains an alkylsulfonyl,arylsulfonyl, alkylsulfinyl or arylsulfinyl group, are prepared by theoxidation of the corresponding compounds of formula I wherein R¹, R², Z,Z¹, Z² and Z³ are as hereinbefore defined and R³ is as hereinbeforedefined and contains an alkylthio or arylthio group, preferably by meansof reaction with a peroxyacid, e.g. 3-chloroperbenzoic acid, preferablyin an inert solvent, e.g. dichloromethane, preferably at or near roomtemperature. Alternatively, the oxidation is carried out by reactionwith a peroxomonosulfate, e.g. potassium peroxomonosulfate, convenientlyin a solvent such as methanol, buffered to about pH 5, at temperaturesbetween about 0° C. and room temperature. This latter method ispreferred for compounds containing an acid-labile group, such as thosewherein the moiety R² O-- contains a carbon-carbon double bond betweenits beta- and gamma-carbon atoms, e.g. a cyclopent-2-enyloxy group.

As another example, compounds of formula I wherein R¹, R², Z, Z¹, Z² andZ³ are as hereinbefore defined, and Z is preferably oxygen, and R³ is ashereinbefore defined and contains a hydroxymethyl group are prepared bythe reduction of the corresponding compounds of formula I wherein R¹,R², Z¹, Z² and Z³ are as hereinbefore defined and R³ is as hereinbeforedefined and contains an aryloxycarbonyl or, preferably, alkoxycarbonylgroup, preferably by means of reaction with an alkali metal borohydride,preferably in an inert solvent, e.g. tetrahydrofuran, preferably at ornear room temperature.

As another example, compounds of formula I wherein R¹, R², Z, Z¹, Z² andZ³ are as hereinbefore defined, Z preferably being an oxygen atom, andR³ is as hereinbefore defined and contains a formyl group are preparedby the oxidation of the corresponding compounds of formula I wherein R¹,R², Z, Z¹, Z² and Z³ are as hereinbefore defined and R³ is ashereinbefore defined and contains a hydroxymethyl group, for example byreaction with oxalyl chloride and dimethyl sulfoxide, in a solvent suchas dichloromethane, and preferably at a temperature lower than -65° C.,or, preferably, by reaction with a complex of sulfur trioxide with anamine such as pyridine, preferably in the presence of an amine such astriethylamine, preferably at or near room temperature.

As another example, compounds of formula I wherein R¹, R², Z, Z¹, Z² andZ³ are as hereinbefore defined, and Z is preferably oxygen, and R³ is ashereinbefore defined and contains an amino group are prepared by thereduction of the corresponding compounds of formula I wherein R¹, R², Z,Z¹, Z² and Z³ are as hereinbefore defined and R³ is as hereinbeforedefined and contains a nitro group, preferably by means of reaction withiron in acidic conditions, e.g. in acetic acid, preferably at or aboveroom temperature, more especially at the reflux temperature.Alternatively the reduction are carried out by reaction with hydrazinehydrate in the presence of ferric chloride and activated carbon,conveniently in a solvent such as methanol, at temperatures betweenabout 25° C. and 80° C. This latter method is preferred for compoundscontaining an acid-labile group, such as those wherein the moiety R² O--contains a carbon-carbon double bond between its beta and gamma-carbonatoms, e.g. a cyclopent-2-enyloxy group.

As another example, compounds of formula I wherein R¹, R², Z, Z¹, Z² andZ³ are as hereinbefore defined, and Z is preferably oxygen, and R³ is ashereinbefore defined and contains an alkanoylamino or aroylamino groupare prepared from compounds of formula I wherein R¹, R², Z, Z¹, Z² andZ³ are as hereinbefore defined and R³ is as hereinbefore defined andcontains an amino group, preferably by means of reaction with theappropriate acid halide or acid anhydride in the presence of a tertiarybase such as triethylamine, optionally in an inert solvent, andpreferably at a temperature from 0° C. to the reflux temperature.

As another example, the compounds of formula I wherein R¹, R², Z, Z¹, Z²and Z³ are as hereinbefore defined, Z, Z¹ and Z² preferably are oxygen,and R³ represents a heteroaryl group containing one or more nitrogenring atoms, can be converted to the corresponding N-oxides preferably bymeans of reaction with a mixture of hydrogen peroxide and an organicacid, e.g. acetic acid, preferably at or above room temperature at60-90° C. Alternatively, the oxidation is carried out by reaction withhydrogen peroxide in the presence of sodium tungstate at temperaturesbetween room temperature and about 60° C. This latter method ispreferred for compounds containing an acid-labile group, such as thosewherein the moiety R² O-- contains a carbon-carbon double bond betweenits beta- and gamma-carbon atoms, e.g. a cyclopent-2-enyloxy group.

For example, compounds of formula I wherein R¹ is as hereinbeforedefined and is substituted on its alpha-carbon atom by fluorine and Z¹is sulfur, and/or wherein R² is as hereinbefore defined and issubstituted on its alpha-carbon atom by fluorine and Z² is sulfur, andR³ and Z³ as hereinbefore defined, are prepared by the reaction of xenondifluoride with corresponding compounds of formula I wherein saidalpha-carbon atoms carry hydrogen atoms instead of said fluorine atoms.The reaction is conveniently carried out in a solvent, such asdichloromethane, in the presence of a molecular sieve, and in an inertatmosphere, at a low temperature, e.g. at or near 0° C.

As another example, compounds of formula I wherein R¹, R², Z, Z¹, Z² andZ³ are as hereinbefore defined, and R³ represents a heteroaryl groupcontaining one or more nitrogen ring atoms but carrying no halogensubstituents, are prepared by the reduction of the correspondingcompounds of formula I wherein R³ does carry one or more halogen, e.g.chlorine, substituents, for example by means of ammonium formate in thepresence of a palladium catalyst.

Compounds of the present invention may contain asymmetric centers. Theseasymmetric centers may independently be in either the R or Sconfiguration. It will be apparent to those skilled in the art thatcertain compounds of the invention may also exhibit geometricalisomerism. The present invention comprises the individual geometricalisomers and stereoisomers and mixtures thereof.

Such isomers can be separated from their mixtures, by the application oradaptation of known methods, for example chromatographic techniques andrecrystallization techniques, or they are separately prepared from theappropriate isomers of their intermediates, for example by theapplication or adaptation of methods described herein.

The compounds of the present invention are useful in the form of thefree base or acid or in the form of a pharmaceutically acceptable saltthereof. All forms are within the scope of the invention.

Where the compound of the present invention is substituted with a basicmoiety, acid addition salts are formed and are simply a more convenientform for use; and in practice, use of the salt form inherently amountsto use of the free base form. The acids which can be used to prepare theacid addition salts include preferably those which produce, whencombined with the free base, pharmaceutically acceptable salts, that is,salts whose anions are non-toxic to the patient in pharmaceutical dosesof the salts, so that the beneficial inhibitory effects on TNF and PDEinherent in the free base are not vitiated by side effects ascribable tothe anions. Although pharmaceutically acceptable salts of said basiccompounds are preferred, all acid addition salts are useful as sourcesof the free base form even if the particular salt, per se, is desiredonly as an intermediate product as, for example, when the salt is formedonly for purposes of purification, and identification, or when it isused as intermediate in preparing a pharmaceutically acceptable salt byion exchange procedures. Pharmaceutically acceptable salts within thescope of the invention are those derived from the following acids:mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acidand sulfamic acid; and organic acids such as acetic acid, citric acid,lactic acid, tartaric acid, malonic acid, methanesufonic acid,ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,cyclohexylsulfamic acid, quinic acid, and the like. The correspondingacid addition salts comprise the following: hydrohalides, e.g.hydrochloride and hydrobromide, sulfate, phosphate, nitrate, sulfamate,acetate, citrate, lactate, tartarate, malonate, oxalate, salicylate,propionate, succinate, fumarate, maleate,methylene-bis-B-hydroxynaphthoates, gentisates, mesylates, isethionatesand di-p-toluoyltartratesmethanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and quinate,respectively.

According to a further feature of the invention, acid addition salts ofthe compounds of this invention are prepared by reaction of the freebase with the appropriate acid, by the application or adaptation ofknown methods. For example, the acid addition salts of the compounds ofthis invention are prepared either by dissolving the free base inaqueous or aqueous-alcohol solution or other suitable solventscontaining the appropriate acid and isolating the salt by evaporatingthe solution, or by reacting the free base and acid in an organicsolvent, in which case the salt separates directly or can be obtained byconcentration of the solution.

The acid addition salts of the compounds of this invention can beregenerated from the salts by the application or adaptation of knownmethods. For example, parent compounds of the invention can beregenerated from their acid addition salts by treatment with an alkali,e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.

Where the compound of the invention is substituted with an acidicmoiety, base addition salts may be formed and are simply a moreconvenient form for use; and in practice, use of the salt forminherently amounts to use of the free acid form. The bases which can beused to prepare the base addition salts include preferably those whichproduce, when combined with the free acid, pharmaceutically acceptablesalts, that is, salts whose cations are non-toxic to the animal organismin pharmaceutical doses of the salts, so that the beneficial inhibitoryeffects on TNF and PDE inherent in the free acid are not vitiated byside effects ascribable to the cations. Pharmaceutically acceptablesalts, including for example alkali and alkaline earth metal salts,within the scope of the invention are those derived from the followingbases: sodium hydride, sodium hydroxide, potassium hydroxide, calciumhydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide,zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine,arginine, omithine, choline, N,N'-dibenzylethylenediamine,chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine,diethylamine, piperazine, tris(hydroxymethyl)-aminomethane,tetramethylammonium hydroxide, and the like.

Metal salts of compounds of the present invention may be obtained bycontacting a hydride, hydroxide, carbonate or similar reactive compoundof the chosen metal in an aqueous or organic solvent with the free acidform of the compound. The aqueous solvent employed may be water or itmay be a mixture of water with an organic solvent, preferably an alcoholsuch as methanol or ethanol, a ketone such as acetone, an aliphaticether such as tetrahydrofuran, or an ester such as ethyl acetate. Suchreactions are normally conducted at ambient temperature but they may, ifdesired, be conducted with heating.

Amine salts of compounds of the present invention may be obtained bycontacting an amine in an aqueous or organic solvent with the free acidform of the compound. Suitable aqueous solvents include water andmixtures of water with alcohols such as methanol or ethanol, ethers suchas tetrahydrofuran, nitrites such as acetonitrile, or ketones such asacetone. Amino acid salts may be similarly prepared.

The base addition salts of the compounds of this invention can beregenerated from the salts by the application or adaptation of knownmethods. For example, parent compounds of the invention can beregenerated from their base addition salts by treatment with an acid,e.g. hydrochloric acid.

As will be self-evident to those skilled in the art, some of thecompounds of this invention do not form stable salts. However, acidaddition salts are most likely to be formed by compounds of thisinvention wherein R³ represents a nitrogen-containing heteroaryl groupand/or wherein R³ contains an amino group as a substituent. Preferableacid addition salts of the compounds of the invention are those whereinR² is other than an acid labile group.

As well as being useful in themselves as active compounds, salts ofcompounds of the invention are useful for the purposes of purificationof the compounds, for example by exploitation of the solubilitydifferences between the salts and the parent compounds, side productsand/or starting materials by techniques well known to those skilled inthe art.

It will be apparent to those skilled in the art that certain compoundsof formula I can exhibit isomerism, for example geometrical isomerismand optical isomerism. Geometrical isomers include the cis and transforms of compounds of the invention having alkenyl or diazenyl moieties.All isomers within formula I, and their mixtures, are within the scopeof the invention.

Such isomers can be separated from their mixtures, by the application oradaptation of known methods, for example chromatographic techniques andrecrystallization techniques, or they are separately prepared from theappropriate isomers of their intermediates, for example by theapplication or adaptation of methods described herein.

The starting materials and intermediates are prepared by the applicationor adaptation of known methods, for example methods as described in theReference Examples or their obvious chemical equivalents.

For example, compounds of formula II, wherein R¹, R², Z¹ and Z² are ashereinbefore defined, are prepared from compounds of formula XXXV##STR31## wherein R¹, R², Z¹ and Z² are as hereinbefore defined, by theapplication or adaptation of known methods for the preparation of acidhalides from carboxylic acids. For example, when X in compound offormula II represents a chloro, the reaction can be carried out by meansof thionyl chloride or, preferably, oxalyl chloride in the presence oftriethylamine.

Compounds of formula XXXV, wherein R¹, R², Z¹ and Z² are as hereinbeforedefined, are prepared by the oxidation of compounds of formula XVIabove, wherein R¹, R², Z¹ and Z² are as hereinbefore defined, e.g. bymeans of reaction with potassium permanganate, or with a mixture ofsulfamic acid and sodium chlorite in acetic acid, or with sodiumchlorite in the presence of sodium dihydrogen phosphate.

Compounds of formula XVI, wherein R¹, R², Z¹ and Z² are as hereinbeforedefined, are prepared from compounds of formula XXXVI ##STR32## whereinR¹, Z¹ and Z² are as hereinbefore defined, by reaction with compounds ofthe formula:

    R.sup.2 X                                                  V

wherein R² and X are as hereinbefore defined, and X is preferably bromo,preferably in the presence of a base, for example an alkali metalhydride, e.g. sodium hydride, an alkali metal hydroxide or carbonate,e.g. sodium hydroxide or carbonate, or an amine, preferably a tertiaryamine, e.g. triethylamine or pyridine, optionally in an inert solvent,for example dichloromethane, dimethylformamide, or an ether, e.g.diethyl ether or tetrahydrofuran, preferably at a temperature from 0° C.to the reflux temperature, or alternatively by reaction with compoundsof the formula XXXVII

    R.sup.2 OH                                                 XXXVII

wherein R² is as hereinbefore defined, preferably in the presence of acompound such as diisopropyl azodicarboxylate.

Alternatively compounds of formula XXXV above, wherein R¹, R², Z¹ and Z²are as hereinbefore defined, are prepared by the hydrolysis of compoundsof formula XXXVIII ##STR33## wherein R¹, R², Z¹ and Z² are ashereinbefore defined, e.g. by reaction with a base, such as an alkalimetal carbonate or bicarbonate in the presence of water, followed byreaction with an aqueous acid such as dilute hydrochloric acid.

Compounds of formula XXXVIII above, wherein R¹, R², Z¹ and Z² are ashereinbefore defined, can be prepared from compounds of formula XXXIX##STR34## where R¹ is as herein before defined, by reaction withcompounds of the formula XXXVII, wherein R² is as hereinbefore defined,preferably in the presence of diisopropyl azodicarboxylate andtriphenylphosphine.

Compounds of formula VI above, wherein R¹, R², R³, Z¹ and Z² are ashereinbefore defined, are prepared by the reaction of compounds offormula XXXX ##STR35## wherein R¹, R², Z¹ and Z² are as hereinbeforedefined and X represents halo, e.g. bromo, with compounds of the formulaXXXXI

    R.sup.3 CH2CHO                                             XXXXI

wherein R³ is as hereinbefore defined, in the presence of a base such asbutyl lithium, preferably at a low temperature.

Alternatively, compounds of formula VI above, wherein R¹, R², R³, Z¹ andZ² are as hereinbefore defined, are prepared by the reaction ofcompounds of formula XVI above, wherein R¹, R², Z¹ and Z² are ashereinbefore defined, with compounds of the formula VIII above,

wherein R³ is as hereinbefore defined, in the presence of a base such aslithium diisopropylamide (usually prepared in situ from butyl lithiumand diisopropylamine), preferably at a low temperature.

For example, phenols and thiophenols of formula XIX above, wherein R¹,R³, Z¹ and Z² are as hereinbefore defined, are prepared by the alkalinehydrolysis of their benzoyl esters, which themselves are prepared byreaction of the benzoyl esters of the corresponding sulfonyl chlorideshaving reacted with compounds of formula III above, wherein R³ is ashereinbefore defined. The said sulfonyl chlorides are prepared by theaction of thionyl chloride on the corresponding sulfonic acids, whichthemselves are prepared by insertion of the sulfo-group into the benzenering by the action of chlorsulfonic acid.

Compounds of formula XXI, wherein R¹, R², Z¹ and Z² are as hereinbeforedefined, are prepared by the reaction of bromine in carbon tetrachlorideand ultraviolet radiation on the corresponding --CHF₂ compounds, whichthemselves are prepared by the action of sulfur tetrafluoride andhydrofluoric acid on compounds of formula XVI above, wherein R¹, R², Z¹and Z² are as hereinbefore defined, in the presence of pyridine.

Compounds of formula XXIX above, wherein R¹, R², Z¹ and Z² are ashereinbefore defined, are prepared by the reaction of selenium dioxideon the corresponding acetophenones in the presence of pyridine.

Compounds of formula XXXIV above, wherein R¹, R², R³, Z¹ and Z² are ashereinbefore defined, are prepared similarly by the reaction of thecorresponding phenylacetaidehyde derivatives with compounds of formulaXXXI above, wherein R³ is as hereinbefore defined, in the presence of abase such as lithium diisopropylamide.

The present invention is further exemplified but not limited by thefollowing illustrative examples which illustrate the preparation of thecompounds according to the invention. The Reference Examples illustratethe preparation of the intermediates.

In the nuclear magnetic resonance spectra (NMR) the chemical shifts areexpressed in ppm relative to tetramethylsilane. Abbreviations have thefollowing significance: s=singlet; d=doublet; t=triplet; m=multiplet;dd=doublet of doublets; ddd=doublet of doublets of doublets; dt=doubletof triplets, b=broad.

EXAMPLE 1

Compounds A,B,C,D,E,F,G,H,I,J K,L,M.N,O,P,Q,R,S,T,U,V,W,X,Y and Z

A stirred solution of 2,6-difluoroaniline (1.52 g) and triethylamine(1.19 g) in dichloromethane (50 mL) at room temperature is treateddropwise with a solution of 3-cyclopentyloxy-4-methoxybenzoyl chloride(3.0 g), that is prepared as described hereinafter in Reference Example3) in dichloro-methane (50 mL). The solution is stirred and heated atreflux for 4 hours, then it is cooled, washed with water and dried overmagnesium sulfate. The solution is concentrated and the resultingresidue is recrystallized from ethyl acetate, to giveN-(2,6-difluorophenyl)-3-cyclopentyloxy-4-methoxybenzamide (1.9 g), m.p.158-160° C. [NMR(CDCl3):1.55-1.7(m,3H),1.8-2.05(m,5H),3.93(s,3H),4.85(m,1H),6.9(d,1H),6.95-7.03(m,2H),7.2-7.3(m,1H),7.35(bs,1H),7.45(q,1H),7.53(d,1H); Elemental analysis: C,65.1; H,5.6; F,10.4;N,4.2%; Calculated: C,65.7; H,5.5; F,10.9; N,4.0%].

By proceeding in a similar manner, but replacing the 2,6-difluoroanilineby the appropriate quantities of the corresponding aniline derivatives,there are prepared:

N-(2-chloro-6-fluorophenyl)-3-cyclopentyloxy-4-methoxybenzamide, m.p.140-142° C. [Elemental analysis: C,62.3; H,5.2; Cl,9.7; N,3.6%;Calculated: C,62.7; H,5.3; Cl,9.75; N,3.85%];

N-(2-trifluoromethylphenyl)-3-cyclopentyloxy-4-methoxybenzamide, m.p.127-129° C. [Elemental analysis: C,63.4; H,5.5; F,13.3; N,3.3%;Calculated: C,63.3; H,5.3; F,15.0; N,3.7%];

N-(2,4,6-trichloropbenyl)-3-cyclopentyloxy-4-methoxybenzamide, m.p. 173°C. [Elemental analysis: C,55.2; H,4.4; Cl,26.4; N,3.1; Calculated:C,55.0; H,4.4; Cl,25.6; N,3.4%];

N-(2,6-dibromophenyl)-3-cyclopentyloxy-4-methoxybenzamide, m.p. 133° C.[Elemental analysis: C,48.5; H,4.0; Br,33.9; N,2.85%; Calculated:C,48.6; H,4.1; Br,34.1; N,3.0%];

N-(2-chloro-6-methylpbenyl)-3-cyclopentyloxy-4-methoxybenzamide, m.p.138-140° C. [Elemental analysis: C,66.3; H,6.2; Cl,10.3; N,3.8%;Calculated: C,66.75; H,6.2; Cl,9.85; N,3.9%];

N-(2,6-dichlorophenyl)-3-cyclopentyloxy-4-methoxybenzamide, m.p.138-140° C. [Elemental analysis: C,59.8; H,5.1; Cl,19.1; N, 3.3%;Calculated: C,60.0; H,5.0; Cl,18.65; N,3.7%];

N-(2-fluorophenyl)-3-cyclopentyloxy-4-methoxybenzamide, m.p. 137° C.[Elemental analysis: C,69.3; H,6.2; F,5.7; N,4.0%; Calculated: C,69.3;H,6.1; F,5.8; N,4.25%];

N-phenyl-3-cyclopentyloxy-4-methoxybenzamide, m.p. 169-173° C.[Elemental analysis: --C, 73.2; H,6.7; N,4.2%; Calculated: C,73.3;H,6.8; N,4.5%];

N-(2-methoxyphenyl)-3-cyclopentyloxy-4-methoxybenzamide, m.p. 132-134°C. [Elemental analysis: C,70.1; H,6.8; N,4.0%; Calculated: C,70.4;H,6.8; N,4.1%];

N-(2-chlorophenyl)-3-cyclopentyloxy-4-methoxybenzamide, m.p. 122-124° C.[Elemental analysis: C,65.8; H,5.8; Cl,10.5; N,3.9%; Calculated: C,66.0;H,5.8; Cl,10.25; N,4.05%];

N-(3-chlorophenyl)-3-cyclopentyloxy-4-methoxybenzamide, m.p. 110-12° C.[Elemental analysis: C,65.9; H,6.5; Cl,9.8; N,3.7%; Calculated: C,66.0;H,5.8; Cl,10.25; N,4.05%];

N-(4-methoxyphenyl)-3-cyclopentyloxy-4-methoxybenzamide, m.p. 182-184°C. [Elemental analysis: C,68.7; H,6.6; N,3.8%; Calculated for C₂₀ H₂₃NO₄ :1/2H₂ O: C,68.55; H,6.9; N,4.0%];

N-(2,6-dimethylphenyl)-3-cyclopentyloxy-4-methoxybenzamide, m.p.130-131° C. [Elemental analysis: C,74.2; H,7.4; N,4.1%; Calculated:C,74.3; H,7.4; N,4.13%];

N-(2-methylthiophenyl)-3-cyclopentyloxy-4-methoxybenzamide, m.p.128-130° C. [Elemental analysis: C,67.6; H,6.5; N,3.9; S,8.9%;Calculated: C,67.2; H,6.5; N,3.9; S,9.0%];

N-(2-bromophenyl)-3-cyclopentyloxy-4-methoxybenzamide, m.p. 126-128° C.[Elemental analysis: C,58.2; H,5.1; Br,20.4; N,3.5%; Calculated: C,58.5;H,5.2; Br,20.5; N,3.6%];

N-(2-methoxycarbonylphenyl)-3-cyclopentyloxy-4-methoxybenzamide, m.p.105-107° C. [Elemental analysis: 68.4; H,6.35; N,3.7%; Calculated: 68.3;6.3; N,3.8%];

N-(2-aminosulfonylphenyl)-3-cyclopentyloxy-4-methoxybenzamide, m.p. 248°C. [Elemental analysis: C,58.0; H,5.5; N,6.9%; Calculated: C,58.45;H,5.7; N,7.2%];

N-(2-benzoylphenyl)-3-cyclopentyloxy-4-methoxybenzamide, m.p. 106-107°C. [Elemental analysis: C,75.5; H,6.3; N,3.3%; Calculated: C,75.2;H,6.1; N,3.4%];

N-(2-cyanophenyl)-3-cyclopentyloxy-4-methoxybenzamide, m.p. 170-172° C.[Elemental analysis: C,71.0; H,6.0; N,8.1%; Calculated: C,75.2; H,6.1;N,3.4%];

N-(2,5-dichlorophenyl)-3-cyclopentyloxy-4-methoxybenzamide, m.p.117-119° C. [Elemental analysis: C,59.7; H,5.0; Cl,18.5; N,3.7%;Calculated: C,60.0; H,5.0; Cl,18.65; N,3.7%];

N-(3-methylphenyl)-3-cyclopentyloxy-4-methoxybenzamide, m.p. 147-149° C.[Elemental analysis: C,73.8; H,7.1; N,4.2%; Calculated: C,73.8; H,7.1;N,4.3%];

N-(2-nitrophenyl)-3-cyclopentyloxy-4-methoxybenzamide, m.p. 130-132° C.[Elemental analysis: C,64.0; H,5.7; N,7.4%; Calculated: C,64.0; H,5.7;N,7.9%];

N-(2-dimethylaminophenyl)-3-cyclopentyloxy-4-methoxybenzamide, in theform of a brown oil [Elemental analysis: C,71.5; H,7.4; N,7.4%;Calculated: C,71.2; H,7.4; N,7.9%];

N-(2-acetylphenyl)-3-cyclopentyloxy-4-methoxybenzamide, m.p. 126-127° C.[Elemental analysis: C,71.0; H,6.6; N,3.9%; Calculated: C,71.4; H,6.6;N,4.0%]; and

N-(2-hydroxyphenyl)-3-cyclopentyloxy-4-methoxybenzamide. m.p. 169-171°C. [Elemental analysis: C,69.5; H,6.5; N,3.9%; Calculated: C,69.7; H6.5;N,4.3%].

EXAMPLE 2

Compound AA

A stirred solution ofN-(2-methylthiophenyl)-3-cyclopentyloxy-4-methoxybenzamide (1.80 g; thatis prepared as described hereinbefore in Example 1) is treated with asolution of 3-chloroperbenzoic acid (3.60 g; 85% pure) indichloromethane (72 mL), dropwise, and then it is stirred at roomtemperature for 5 hours. The reaction mixture is washed with saturatedaqueous sodium bicarbonate solution and then with water, and then it isdried over magnesium sulfate. The mixture is concentrated to giveN-(2-methylsulfonylphenyl)-3-cyclopentyloxy-4-methoxybenzamide, (1.12g), in the form of a white solid, m.p. 119-121° C. [NMR(CDCl₃):1.52-2.16 (m,8H), 3.1 (s,3H),3.94(s,3H),4.9(m,1H),6.96(d,1H),7.46(m,1H),7.6(m,2H),7.7(t,1H), 7.95(d,1H),8.68(d,1H); Elemental analysis:C,61.6; H,6.0; N,3.5; S,8.5%; Calculated: C,61.7; H,5.95; N,3.6;S,8.5%].

EXAMPLE 3

Compounds AB AC and AD

By proceeding in a manner similar to that described hereinbefore inExample 1, but using the appropriate quantities of the correspondingacid chlorides, which are prepared as described hereinafter in ReferenceExample 3, there are prepared:

N-(2,6-difluorophenyl)-3-cyclohexyloxy-4-methoxybenzamide, m.p. 60° C.[Elemental analysis: C,66.1; H,6.3; N,3.3%; Calculated: C,66.5; H.,5.9;N,3.9%];

N-(2,6-difluorophenyl)-3-butoxy-4-methoxybenzamide, m.p. 150-152° C.[Elemental analysis: C,64.6; H,5.8; N,4.2; Calculated: C,64.5; H,5.7;N,4.2%]; and

N-(2,6-difluorophenyl)-3-propoxy-4-methoxybenzamide, m.p. 170-174° C.[Elemental analysis: C,63.4; H,5.4; N,4.4%; Calculated: C,63.5; H,5.3;N,4.4%].

EXAMPLE 4

Compound AE

3-Cyclopentyloxy-4-methoxybenzoyl chloride (13.3 g) and 2-chloroaniline(6.6 g) are dissolved in pyridine (50 mL) and the solution is allowed tostand at room temperature for 1 hour. Phosphorus pentasulfide (13 g) isadded and the stirred mixture is heated at 110° C. for 1.5 hours. Aftercooling to room temperature the mixture is poured into an ice-coldsolution of concentrated hydrochloric acid (100 mL) in water (400 mL).The mixture is stirred for 1 hour and the yellow solid is collected,washed with water and subjected to flash chromatography on silica gel,eluting with a mixture of cyclohexane and ethyl acetate (3:1 v/v), togive N-(2-chlorophenyl)-3-cyclopentyloxy-4-methoxy(thiobenzamide) (5.4g), m.p. 129-131° C. [Elemental analysis: C,62.6; H,5.5; N,3.9; S,8.9%;Calculated: C,63.1; H,5.6; N,3.9; S,8.9%].

EXAMPLE 5

Compounds AF, AG, AH, Al, AJ, AK, AL, AM and AN

A stirred solution of 4-chloropyrid-3-ylamine (1.94 g) and3-cyclopentyloxy-4-methoxybenzoyl chloride (3.85 g) in pyridine (50 mL)is heated at 80° C. for 7 hours and then it is allowed to standovernight. The reaction mixture is evaporated, to give a brown oil,which is subjected to mplc on silica gel, using diethyl ether as eluent,to give N-(4-chloropyrid-3-yl)-3-cyclopentyloxy-4-methoxybenzamide (3.1g), m.p. 130-132° C.

By proceeding in a similar manner, but using the appropriate quantitiesof the appropriate amines instead of the 4-chloropyrid-3-ylamine used asa starting material, there are prepared:

N-pyrid-2-yl-3-cyclopentyloxy-4-methoxybenzamide, m.p. 92-94° C.;

N-pyrazin-2-yl-3-cyclopentyloxy-4-methoxybenzamide, m.p. 80-82° C.;

N-pyrimidin-2-yl-3-cyclopentyloxy-4-methoxybenzamide, m.p. 108-110° C.;

N-(3-methylpyrid-2-yl)-3-cyclopentyloxy-4-methoxybenzamide, m.p. 55° C.;

N-pyrid-3-yl-3-cyclopentyloxy-4-methoxybenzamide, m.p. 170-172° C.;

N-(3-chloropyrid-2-yl)-3-cyclopentyloxy-4-methoxybenzamide, m.p.138-140° C.;

N-(3-chloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide, m.p.124-126° C.; and

N-pyrid-4-yl-3-cyclopentyloxy-4-methoxybenzamide, m.p. 163-165° C.

EXAMPLE 6

Compound AO

4-Amino-3,5-dichloropyridine (4.0 g) and3-cyclopentyloxy-4-methoxybenzoyl chloride (6.26 g) are intimatelyground together in a mortar with a pestle, and transferred to around-bottomed flask. The mixture is melted, using a hot air gunexternal to the flask, stirring with a magnetic stirrer. After 10minutes, heating is ceased and the melt is allowed to cool. Theresulting material is triturated with dichloromethane and the residualsolid is filtered off. The filtrate is concentrated to give a fawnsolid, which is subjected to flash chromatography on silica gel, elutingwith diethyl ether, to giveN-(3,5-dichloro-pyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide (1.87g), m.p. 155-157° C. [Elemental analysis: C,56.3; H,4.7; N,7.2;Cl,18.4%; calculated: C,56.7; H,4.76; N,7.35; Cl,18.6%; IR spectrum:1661 cm⁻¹, 3244 cm⁻¹ ].

Alternatively, a suspension of 3-cyclopentyloxy-4-methoxybenzamide (2.58g; that is prepared as described in Reference Example 73) in dry toluene(40 mL) is heated at reflux and treated with potassium t-butoxide (1.4g), followed by 3,4,5-trichloro-pyridine (1.82 g). The mixture is thenheated at reflux for 3 hours and 45 minutes, and is then treated with afurther quantity of potassium t-butoxide (1.4 g) and heated at refluxfor a further period of 7 hours. The mixture is allowed to cool and isthen filtered. The filtrate is evaporated and the resulting residue isextracted with aqueous sodium hydroxide solution (2 M). The alkalinesolution is then acidified by treatment with acetic acid, and the solidwhich separates is collected by filtration, washed with water and dried,to give N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxy-benzamide(2.09 g) in the form of a buff solid, m.p. 153-155° C.

EXAMPLE 7

Compound AP

By proceeding in a manner similar to that described hereinbefore inExample 1, but replacing the 2,6-difluoroaniline that is used as astarting material by the appropriate quantity of4-amino-3,5-dimethylisoxazole, there is preparedN-(3,5-dimethylisoxazol-4-yl)-3-cyclopentyloxy-4-methoxy-benzamide, m.p.150-152° C. [Elemental analysis: C,65.6; H,6.8; N,8.5%; calculated:C,65.4; H,6.7; N,8.5% 11].

EXAMPLE 8

Compounds AO, AY, BC, BG, BL, BQ, BS, BX, AX, AZ, AW, BV, BW, DF, DG,DH, DI, DJ, DK, DL, DM and DN

A suspension of sodium hydride (60% dispersion in oil; 2.2 g) in drytetrahydrofuran (25 mL) at 15-20° C. is treated portionwise with asolution of 4-amino-3,5-dichloropyridine (4.5 g; that is prepared asdescribed in Reference Example 5) in dry tetrahydrofuran (40 mL), withcooling. The mixture is stirred for a further 30 minutes, and then it iscooled to 10° C. and treated with a solution of3-cyclopentyloxy-4-methoxybenzoyl chloride (6.4 g) in drytetrahydrofuran (40 mL), dropwise, during 45 minutes at 10° C. Themixture is stirred at 10° C. for 30 minutes and is then treated withdilute hydrochloric acid (50 mL; 1 N), followed by dichloromethane (75mL). The layers are separated and the aqueous layer is washed with afurther quantity of dichloromethane (25 mL). The combined organic layersare washed with water (50 mL), with saturated aqueous sodium bicarbonatesolution (100 mL), and with water (50 mL), dried over magnesium sulfateand evaporated to dryness. The resulting residue is recrystallized fromisopropanol, to giveN-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide (7.0 g).

By proceeding in a similar manner, but using the appropriate quantitiesof the corresponding benzoyl halides and amines as starting materials,and optionally using dimethylformamide instead of tetrahydrofuran, thereare prepared:

N-(3,5-dibromopyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide, m.p.160-162° C. [Elemental analysis: C,46.4; H,3.9; N,6.1%; calculated:C,46.0; H,3.9; N,6.0%];

N-(3,5-dimethylpyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide, m.p.77-80° C. [Elemental analysis: C,67.2; H,6.9; N,7.8%; calculated:C,67.0; H,7.3; N,7.8%];

N-(2,6-dichloro-4-cyanophenyl)-3-cyclopentyloxy-4-methoxybenzamide, m.p.170-172° C. [Elemental analysis: C,59.1; H,4.5; N,7.0; Cl,17.5%;calculated: C,59.3; H,4.5; N,6.9; Cl,17.5%];

N-(2,6-dichloro-4-methoxycarbonylphenyl)-3-cyclopentyloxy-4-methoxybenzamide,m.p. 158-160° C. [Elemental analysis: C,57.4; H,4.9; N,3.2; Cl,16.4%;calculated: C,57.5; H,4.8; N,3.2; Cl,16.2%];

N-(2,3,5-trifluoropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide, m.p.144-146° C. [Elemental analysis: C,59.3; H,4.9; N,7.5%; calculated:C,59.0; H,4.7; N,7.65%];

N-(2,6-dichloro-4-ethoxycarbonylphenyl)-3-cyclopentyloxy-4-methoxybenzamide,m.p. 164-166° C.;N-(2,6-dichloro-4-nitrophenyl)-3-cyclopentyloxy-4-methoxybenzamide, m.p.154-156° C.;

N-(3,5-dichloropyrid-4-yl)-3-cyclohexyloxy-4-methoxybenzamide, m.p. 170°C. [Elemental analysis: C,57.8; H,5.1; N,7.0; Cl,17.8%; calculated:C,57.7; H,5.1; N,7.1; Cl,17.9%];

N-(3,5-dichloropyrid-4-yl)-3-butoxy-4-methoxybenzamide, m.p. 165-167° C.[Elemental analysis: C,55.1; H,4.8; N,7.6; Cl,19.2%; calculated: C,55.3;H,4.9; N,7.6; Cl,19.2%];

N-(3,5-dichloropyrid-4-yl)-3-(exo-8,9,10-trinorbornyl-2-oxy)-4-methoxybenzamide,m.p. 149-150° C. [Elemental analysis: C,58.8; H,4.9; N,6.7%; calculated:C,59.0; H,5.0; N,6.9%];

(R)-N-(3,5-dichloropyrid-4-yl)-3-(exo-8,9,10-trinorbornyl-2-oxy)-4-methoxybenzamide,m.p. 155-156° C. [Elemental analysis: C,58.8; H,5.0; N,6.8%];

(S)-N-(3,5-dichloropyrid-4-yl)-3-(exo-8,9,10-trinorbornyl-2-oxy)-4-methoxybenzamide,m.p. 156-157° C.;

3-cyclopentyloxy-N-(3,5-difluoropyrid-4-yl)-4-methoxybenzamide, m.p.160-161° C. [Elemental analysis: C,61.7; H,5.2; N,8.0%; calculated:C,62.1; H,5.2; N,8.0%];

(R)-N-(2,6-dichlorophenyl)-3-(exo-8,9,10-trinorbornyl-2-oxy)-4-methoxy-benzamide,m.p. 144-145° C. [Elemental analysis: C,61.7; H,5.1; N,3.3%; calculated:C,62.1; H,5.2; N,3.45%];

(S)-N-(2,6-dichlorophenyl)-3-(exo-8,9,10-trinorbornyl-2-oxy)-4-methoxy-benzamide,m.p. 143-144° C. [Elemental analysis: C,62.1; H,5.2; N,3,1%; calculated:C,62.1; H,5.2; N,3.45%];

3-cyclopentylmethoxy-N-(3,5-dichloropyrid-4-yl)-4-methoxybenzamide, m.p.192-200° C. [Elemental analysis: C,58.1; H,5.1; N,7.1%; calculated:C,57.7; H,5.1; N,7.1%];

3-cyclopropylmethoxy-N-(3,5-dichloropyrid-4-yl)-4-methoxybenzamide, m.p.226-230° C. [Elemental analysis: C,55.3; H,4.4; N,7.4%; calculated:C,55.6; H,4.4; N,7.6%];

N-(3-bromo-5-chloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide, m.p.132-134° C. [Elemental analysis: C,50.8; H,4.2; N,6.5%; calculated:C,50.8; H,4.3; N,6.6%];

N-(3,5-dichloropyrid-4-yl)-3-isopropoxy-4-methoxybenzamide, m.p.175-176° C. [Elemental analysis: C,54.3; H,4.6; N,8.0%; calculated:C,54.1; H,4.5; N,7.9%];

3-tert-butoxy-N-(3,5-dichloropyrid-4-yl)-4-methoxybenzamide, m.p.148-150° C. [Elemental analysis: C,55.3; H,4.95; N,7.5%; calculated:C,55.3; H,4.9; N,7.6%]; and

N-(3,5-dichloropyrid-4-yl)-4-methoxy-3-(pent-3-yloxy)benzamide, m.p.133-134° C. [Elemental analysis: C,56.5; H,5.25; N,7.3; Cl,18.4%;calculated: C,56.4; H,5.26; N,7.3; Cl, 18.5%].

EXAMPLE 9

Compound AV

A stirred suspension ofN-(3,5-dichloropyrid-4yl)-3-cyclopentyloxy-4-methoxybenzamide (2.0 g;that is prepared as described in Example 6) in glacial acetic acid (8mL) is treated with an aqueous solution of hydrogen peroxide (6 mL;27.5%). The mixture is stirred for 3 hours at 70-80° C. and then it istreated with a further portion of hydrogen peroxide solution (4 mL), andthe solution is stirred for a further 12 hours. The solution is thencooled, basified by treatment with concentrated aqueous sodium hydroxidesolution, and extracted with dichloromethane (2×30 mL). The organicextract is washed with brine (30 mL), dried over magnesium sulfate andevaporated. The resulting residue recrystallized from ethyl acetate, togive3,5-dichloro-4-(3-cyclopentyloxy-4-methoxybenzamido)pyridine-N-oxide(0.73 g), m.p. 118-120° C. [Elemental analysis: C,53.0; H,4.4; N,6.8%;calculated for C₁₈ H₁₈ O₄ N₂ Cl₂ :0.5H₂ O: C,53.2; H 4.7; N 6.9%].

EXAMPLE 10

Compound BE

A stirred solution ofN-(3,5-dichloropyrid-4yl)-3-cyclopentyloxy-4-methoxybenzamide (2.0 g;that is prepared as described in Example 6) in toluene (50 mL) istreated with2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (3.0g), and the mixture is heated at 100° C. for 2 hours. After cooling toroom temperature and filtration, the filtrate is concentrated in vacuo,to give a yellow oil. This oil is subjected to flash chromatography onsilica gel, using a mixture of pentane and ethyl acetate (8:2 v/v) aseluent, to giveN-(3,5-dichloropyrid-4-yl)3-cyclopentyloxy-4-methoxy(thiobenzamide)(0.64 g)m.p. 118-119° C. [Elemental analysis: C,54.1; H,4.6; Cl,17.4;N,6.8%; calculated: C,54.4; H,4.6; Cl,17.85; N,7.05%].

EXAMPLE 11

Compound BI

A solution ofN-(2,6-dichloro-4-nitrophenyl)-3-cyclopentyloxy-4-methoxybenzamide (1.5g; that is prepared as described in Example 8) in glacial acetic acid(22 mL) is treated with iron pin dust (1.3 g) and the mixture is heatedwith stirring at 90° C. for 1 hour. The reaction mixture is cooled,basified to pH 8 by treatment with saturated aqueous sodium carbonatesolution, and extracted with ethyl acetate (2×150 mL). The combinedorganic extract is dried over magnesium sulfate and concentrated invacuo, to give a white solid. This solid is subjected to flashchromatography, eluting with a mixture of ethyl acetate and pentane (1:1v/v), to giveN-(2,6-dichloro-4-aminophenyl)-3-cyclopentyloxy-4-methoxybenzamide (0.8g), m.p. 170-172° C. [Elemental analysis: C,54.8; H,5.04; N,6.5;Cl,17.4%; calculated: C,57.7; H,5.1; N,7.1; Cl,17.9%].

EXAMPLE 12

Compound BM

Acetic anhydride (10 mL) is treated withN-(2,6-dichloro-4-aminophenyl)-3-cyclopentyloxy-4-methoxybenzamide (0.8g; that is prepared as described in Example 11), and the reactionmixture is stirred for 2 hours and left to stand overnight. It is thenpoured into water (100 mL), and extracted with ethyl acetate (100 mL)and then with dichloromethane (100 mL). The organic extracts arecombined, dried over magnesium sulfate, and evaporated, to giveN-(4-acetylamino-2,6-dichlorophenyl)-3-cyclopentyloxy-4-methoxybenzamide(0.4 g), m.p. 250-252° C. [Elemental analysis: C,57.6; H,5.05; N,6.3;Cl,6.1%; calculated: C,57.5; H,5.1; N,6.4; Cl, 16.2%].

EXAMPLE 13

Compounds BN and BU

A stirred solution ofN-(3,5-dichloropyrid-4-yl)-3-hydroxy-4-methoxybenzamide (2.0 g; that isprepared as described in Reference Example 12) in dimethylformamide (20mL) at room temperature under nitrogen is treated portionwise with asuspension of sodium hydride (60% dispersion in oil; 0.26 g), and thenit is stirred for a further hour at room temperature. It is then treateddropwise with 1-bromononane (1.2 mL) and stirred at 60° C. for 5 hours.The solution is then cooled to room temperature, diluted with water (60mL), and extracted with ethyl acetate (2×100 mL). The combined organicextracts are dried over magnesium sulfate and evaporated, to give awhite solid, which is subjected to flash chromatography on silica gel,eluting with t-butyl methyl ether, to giveN-(3,S-dichloropyrid-4-yl)-3-nonyloxy-4-methoxybenzamide (0.56 g), m.p.151-153° C. [Elemental analysis: C,60.3; H,6.45; N,6.3%; calculated:C,60.1; H,6.4; N,6.4%].

By proceeding in a similar manner, but using the appropriate quantity of1-bromododecane, there is preparedN-(3,5-dichloropyrid-4-yl)-3-dodecyloxy-4-methoxybenzamide, m.p.143-145° C.

EXAMPLE 14

Compound BO

A solution ofN-(2,6-dichloro-4-hydroxymethylphenyl)-3-cyclopentyloxy-4-methoxybenzamide(4.4 g) in dichloromethane (30 mL) is treated with activated manganesedioxide (6.2 g), and the mixture is stirred at reflux for 24 hours. Themixture is filtered, the filtrate is evaporated, and the resultingresidue is subjected to flash chromatography on silica gel, eluting withethyl acetate, to giveN-(2,6-dichloro-4-formylphenyl)-3-cyclopentyloxy-4-methoxybenzamide (2.4g), m.p. 96-98° C. [Elemental analysis: C,59.0; H,5.1; N,3.1%;calculated: C,58.8; H,4.7; N,3.4%].

EXAMPLE 15

Compound BT

A stirred solution ofN-(2,6-dichloro-4-ethoxycarbonylphenyl)-3-cyclopentyloxy-4-methoxybenzamide(6.1 g; that is prepared as described in Example 8) in drytetrahydrofuran (80 mL) at room temperature under argon is treateddropwise with a solution of lithium borohydride in tetrahydrofuran (115mL; 2 M). The mixture is stirred overnight and then it is treatedportionwise with saturated brine (200 mL) and stirred for 30 minutes.The organic layer is then washed with water, dried over magnesiumsulfate and evaporated. The resulting residue is subjected to flashchromatography on silica gel, to giveN-(2,6-dichloro-4-hydroxymethylphenyl)-3-cyclopentyloxy-4-methoxybenzamide(4.4 g), m.p. 174-176° C. [Elemental analysis: C,57.1; F1,5.4; N,2.9%;calculated C₂₀ H₂₁ O₄ NCl₂ :0.5H₂ O: C,57.3; H,5.3; N,3.3%].

EXAMPLE 16

Compound BR

A solution ofN-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide (3.8 g;that is prepared as described in Example 6) in dry tetrahydrofuran (25mL) is treated with a suspension of sodium hydride (60% dispersion inoil; 0.40 g), and the mixture is stirred until effervescence has ceasedand a solution has formed. This solution is evaporated in vacuo and theresulting residue is triturated with t-butyl methyl ether (20 mL). Theresulting off-white solid is filtered off, quickly washed with t-butylmethyl ether (2×20 mL) and dried, to give the sodium salt ofN-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxy-benzamide (3.5 g),m.p. 265-270° C. (with decomposition) [NMR(DMSO-D₆):1.52-1.93(m,8H),4.77(s,3H),4.75-4.80(m,1H),6.98(d,1H),7.58(dd,1H),7.60(s,1H),8.20(s,2H); IR spectrum: strongpeak at 1508 cm⁻¹, with no peaks at or near 1661 cm⁻¹ nor 3244 cm⁻¹,which would have been characteristics of the starting material].

EXAMPLE 17

Compounds AU BF and BP

By proceeding in a manner similar to that described in Example 5, butreplacing the 4-chloropyrid-3-ylamine that is used as a startingmaterial by the appropriate quantities of the corresponding anilinederivatives, there are prepared:

N-(2,4,6-trifluorophenyl)-3-cyclopentyloxy-4-methoxybenzamide, m.p.160-162° C. [Elemental analysis: C,62.5; H,5.0; N,3.6%; calculated:C,62.5; H,5.0; N,3.8%]; and

N-(2,6-dichloro-4-methoxyphenyl)-3-cyclopentyloxy-4-methoxybenzamide,m.p. 126-128° C. [Elemental analysis: C,57.9; H,4.9; N,3.2%; calculated:C,58.5; H,5.2; N,3.4%].

By again proceeding in a similar manner, but replacing the4-chloropyrid-3-ylamine and the 3-cyclopentyloxy-4-methoxybenzoylchloride by the appropriate quantities of 2,6-dichloroaniline and3-(exo-8,9,10-trinorbornyl-2-oxy)-4-methoxybenzoyl chloride (that isprepared as described in Reference Example 14), there is preparedN-(2,6-dichlorophenyl)-3-(exo-8,9,10-trinorbornyl-2-oxy)-4-methoxybenzamide,m.p. 106-107° C. [Elemental analysis: C,61.8; H,5.2; N,3.2%; calculated:C,62.1; H,5.2; N,3.45%].

EXAMPLE 18

Compounds AQ, AS, AT, BD, BH, BJ and BK

By proceeding in a manner similar to that described in Example 6, butreplacing the 4-amino-3,5-dichloropyridine that is used as a startingmaterial by the appropriate quantities of the corresponding amines,there are prepared:

N-(4,6-dichloropyrimid-5-yl)-3-cyclopentyloxy-4-methoxybenzamide, m.p.191-193° C. [Elemental analysis: C,53.1; H,4.4; Cl,18.6; N,10.9%;calculated: C,53.1; H,4.5; Cl,18.6; N,10.8%];

N-(2,3,5,6-tetrafluoropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide,m.p. 178-180° C. [Elemental analysis: C,56.0; H,4.1; N,7.2%; calculated:C,56.25; H,4.2; N,7.3%];

N-(3,5-dichloro-2,6-difluoropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide,m.p. 188-190° C. [Elemental analysis: C,51.5; H,3.8; N,6.8; Cl,17.0%;calculated: C,51.8; H,3.9; N,6.7; Cl,17.0%];

N-(5-cyano-3-methylisothiazol-4-yl)-3-cyclopentyloxy-4-methoxybenzamide,m.p. 163-164° C. [Elemental analysis: C,60.0; H,5.3; N,11.7%;calculated: C,60.5; H,5.85; N,11.8%];

N-(2,6-dichloro-4-carbamoylphenyl)-3-cyclopentyloxy-4-methoxybenzamide,m.p. 245-247° [Elemental analysis: C,54.0; H,4.5; N,6.4%; calculated:C,54.4; H,5.0; N,6.35%]; and

N-(3-chloro-2,5,6-trifluoropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide,m.p. 188-190° C. [Elemental analysis: C,53.7; H,3.95; N,6.81; Cl,8.9%;calculated: C,53.94; H,4.0; N,7.0; C₁,8.85 %].

By again proceeding in a similar manner, but replacing the4-amino-3,5-dichloropyridine and the 3-cyclopentyloxy-4-methoxybenzoylchloride by the appropriate quantities of 4-amino-3,5-dibromopyridineand 3-butoxy-4-methoxybenzoyl chloride (that is prepared as described inReference Example 3), there is preparedN-(3,5-dibromopyrid-4-yl)-3-butoxy-4-methoxybenzamide, m.p. 160-162° C.[Elemental analysis: C,44.6; H,3.9; N,6.1%; calculated: C,44.6; H,4.0;N,6.1%].

EXAMPLE 19

Compounds AR, BA and BB

By proceeding in a manner similar to that described in Example 1, butreplacing the 2,6-difluoroaniline that is used as starting material bythe appropriate quantities of the corresponding amines, there areprepared: N-(4-nitrophenyl)-3-cyclopentyloxy-4-methoxybenzamide, m.p.178-180° C. [Elemental analysis: C,64.1; H,5.7; N,7.5%; calculated:C,64.0; H,5.7; N,7.9%];

N-(3-methyl-5-bromoisothiazol-4-yl)-3-cyclopentyloxy-4-methoxybenzamide,m.p. 160-162° C. [Elemental analysis: C,50.0; H,4.7; N,6.8%; calculated:C,49.6; H,4.7; N,6.8%]; and

N-(3,5-dimethylisothiazol-4-yl)-3-cyclopentyloxy-4-methoxybenzamide,m.p. 140-141° C. [Elemental analysis: C,62.4; H,6.35; N,8.0%;calculated: C,62.4; H,6.4; N,8.1%].

EXAMPLE 20

Compound BY

A solution of 4-amino-3,5-dichloropyridine (0.46 g) in drydimethylformamide (20 mL) is treated with sodium hydride (0.23 g of a60% dispersion in mineral oil; 2.8 mmol) and the mixture is stirred for20 minutes. It is then treated with a solution of3-cyclopentyloxy-4-(methylthio)benzoyl chloride (0.76 g; that isprepared as described in Reference Example 20 in dimethylformamide (10mL) and stirred at 60° C. for 2 hours. The solution is then concentratedand the resulting residue is partitioned between water (30 mL) and ethylacetate (50 mL). The aqueous layer is extracted with ethyl acetate (50mL) and the combined organic layers are dried, concentrated, andsubjected to flash chromatography on silica gel, eluting with a mixtureof diethyl ether and pentane (1:1 v/v), to giveN-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-(methylthio)benzamide (0.7g) in the form of a white crystalline solid, m.p. 157-159° C. [NMR(CDCl₃):8.57 (s,2H), 7.69 (bs,1H), 7.47 (dd,1H,J=8 Hz,J=2 Hz), 7.43(d,1H,J=2 Hz), 7.17 (d,1H,J=8 Hz), 4.95 (m,1H), 2.46 (s,3H),1.98-1.6(m,8H): Elemental analysis: C,54.0; H,4.5; N,7.0; Cl,17.8%;calculated: C,54.4; H,4.6; N,7.05; Cl,17.85%].

EXAMPLE 21

Compound BZ

As in Example 20 but using 4-amino-3,5-difluoropyridine instead of4-amino-3,5-dichloropyridine,N-(3,5-difluoropyrid-4-yl)-3-cyclopentyloxy-4-(methylthio)benzamide issynthesized; m.p. 174-5° C. [Elemental analysis: C,59.4; H,5.1; N,7.6;S,8.3%; calculated: C,59.3; H,5.0; N,7.7; S,8.3%].

EXAMPLE 22

Compounds CA, CB and CC

A solution of 4-amino-3,5-dichloropyridine (1.6 g) in drytetrahydrofuran (20 mL) at 0° C. under nitrogen is treated with sodiumhydride (1 g of a 60% dispersion in mineral oil) and then stirred for afurther 30 minutes at this temperature. It is then treated with asolution of 3-(exo)-8,9,10-trinorbornyl-2-oxy-4-(methylthio)benzoylchloride (2.8 g, that is prepared as described in Reference Example 21)in dry tetrahydrofuran (20 mL) keeping the temperature below 10° C. Theresulting mixture is further stirred in the cold for 1 hour, allowed towarm to room temperature and left to stand overnight. The mixture isthen quenched with 10% aqueous ammonium chloride solution (150 mL), thelayers separated and the aqueous layer further extracted with ethylacetate (2×100 mL). The combined organic extracts are dried (Na₂ SO₄)and evaporated to dryness. The resulting residue is subjected to flashchromatography on silica gel, eluting with ethyl acetate/pentane(gradient elution 1:4 v/v to 1:1 v/v) to giveN-(3,5-dichloropyrid-4-yl)-3-(exo)-8,9,10-trinorbornyl-2-oxy-4-(methylthio)benzamide(2.0 g) as an off white solid, m.p. 175-177° C. (from isopropanol).[Elemental analysis: C,56.7; H,4.8; N,6.6%; calculated: C,56.7; H,4.8;N,6.6%].

By proceeding in a similar manner, but replacing the3-(exo)-8,9,10-trinorbornyl-2-oxy-4-(methylthio)benzoyl chloride that isused as a starting material by the appropriate benzoyl chloridederivatives (that is prepared as described in Reference Example 21)there is prepared:

(R)-N-(3,5-dichloropyrid-4-yl)-3-(exo)-8,9,10-trinorbornyl-2-oxy-4-(methylthio)benzamide,m.p. 185-186° C. (from ethyl acetate/t-butylmethyl ether), [a]_(D) ²¹-19.5° (c=0.91, CH₂ Cl₂). [Elemental analysis: C,56.6; H1,4.9; N,6.6%;Calculated: C,56.7; H,4.8; N,6.6%]; and

(S)-N-(3,5-dichloropyrid-4-yl)-3-(exo)-8,9,10-trinorbornyl-2-oxy-4-(methylthio)benzamide,m.p. 188-189° C. (from ethyl acetate/heptane) [a]_(D) ²⁰ +15.6° (c=1.24,CH₂ Cl₂). [Elemental analysis: C,57.0; H,4.9; N,6.7%; Calculated:C,56.7; H,4.8; N,6.6%].

EXAMPLE 23

Compound CD

A solution of 4-amino-3,5-dichloropyridine (3.73 g) in drytetrahydrofuran (50 mL) under nitrogen at 5-10° C. is treatedportionwise with sodium hydride (60% dispersion in oil; 1.87 g). After30 minutes it is treated dropwise with a solution of3-cyclopent-2-enyloxy-4-methoxybenzoyl chloride in dry tetrahydrofuran(50 mL; that is prepared, as described in Reference Example 30, from5.89 g 3-cyclopent-2-enyloxy-4-methoxybenzoic acid). The resultingmixture is allowed to warm to room temperature and left to standovernight. Most of the solvent is then removed under reduced pressureand the residue is partitioned between water (250 ml,) anddichloromethane (250 mL) and the aqueous layer is further extracted withdichloromethane (2×250 mL). The combined organic layers are dried oversodium sulfate, the solvent is removed under reduced pressure, and theresulting residue is subjected to flash chromatography on silica gel,eluting with mixtures of ethyl acetate and pentane (3:7 to 1:1 v/v), togive a cream solid (1.25 g), which is recrystallized from a mixture ofethyl acetate and pentane, to give(±)-N-(3,5-dichloropyrid-4-yl)-3-cyclopent-2-enyloxy-4-methoxybenzamide(0.80 g), as a white solid, m.p. 177-178° C. [Elemental analysis:C,56.9; H,4.2; N,7.4; Cl,18.6%; calculated: C,57.0; H,4.3; N,7.4;Cl,18.7%].

EXAMPLE 24

Compound CE

A solution of 4-amino-3,5-dichloropyridine (0.93 g) in drytetrahydrofuran (56 mL) under nitrogen at 5-10° C. is treatedportionwise with sodium hydride (60% dispersion in oil, 0.57 g). After 1hour it is treated dropwise with a solution of3-cyclopent-3-enyloxy-4-methoxybenzoyl chloride in dry tetrahydrofuran(30 mL) prepared as described in Reference Example 33 from 1.33 g3-cyclopent-3-enyloxy-4-methoxybenzoic acid). The resulting mixture isallowed to warm to room temperature, stirred for a further 3 hours andthen poured into 5% aqueous potassium carbonate (430 mL). The resultingemulsion is extracted with ethyl acetate (3×150 mL), the combinedorganic extracts washed with water (2×20 mL), followed by ice-cold 1 Maqueous hydrochloric acid (2×20 mL) and dried over sodium sulfate. Thesolvent is removed under reduced pressure and the resulting residuesubject to flash chromatography on silica gel, eluting with mixtures oft-butyl methyl ether and cyclohexane (2:3 to 7:3 v/v), to give a creamsolid, which is recrystallized from acetonitrile to giveN-(3,5-dichloropyrid-4-yl)-3-cyclopent-3-enyloxy-4-methoxybenzamide(0.54 g), as a white solid, m.p. 193-195° C. [Elemental analysis:C,56.7; H,4.2; N,7.3%; calculated: C,57.0; H,4.3; N,7.4%].

EXAMPLE 25

Compound CF

A solution of 4-amino-3,5-dichloropyridine (0.27 g) in tetrahydrofuran(7 mL) under nitrogen is treated with sodium hydride (60% dispersion inoil; 0.13 g; 3.2 mmol), portionwise, and stirred at room temperature for15 minutes. It is then treated dropwise with a solution of3-cyclopentyloxy-4-difluoromethoxy-benzoyl chloride (0.48 g; that isprepared as described in Reference Example 43) in tetrahydrofuran (5 mL)and the reaction mixture is stirred at room temperature for 3 hours.Tetrahydrofuran is evaporated off under reduced pressure and the cruderesidue is partitioned between water (40 mL) and ethyl acetate (40 mL).The organic layer is separated and the aqueous layer is extracted with afurther quantity of ethyl acetate (40 mL). The combined ethyl acetateextracts are dried over magnesium sulfate, evaporated under reducedpressure and subjected to flash chromatography on silica gel, using amixture of diethyl ether and pentane (2:3 v/v), to giveN-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-difluoro-methoxybenzamide(0.51 g), in the form of a white solid, m.p. 127-129° C. [Elementalanalysis: C,51.9; H,3.88; N,6.48%; calculated: C,51.82; H,3.86,N,6.71%].

EXAMPLE 26

Compound CG

A suspension of sodium hydride (60% dispersion in oil; 3.2 g; 80 mmol)in dry tetrahydrofuran (70 mL) under nitrogen at 4° C. is treated with3,5-dichloro-4-aminopyridine (6.5 g) in dry tetrahydrofuran (80 mL)during 15 minutes and the solution is stirred at room temperature for 1hour. After cooling to 5° C., it is treated with3-cyclopentylthio-4-methoxybenzoyl chloride (that is prepared from 9.0 gof 3-cyclopentylthio-4-methoxybenzoic acid as described in ReferenceExample 47) in dry tetrahydrofuran (80 mL) during 45 minutes, and thetemperature is allowed to rise to room temperature. The mixture istreated with a further quantity of tetrahydrofuran (200 mL) and then itis stirred for a further 6 hours. It is then treated with a saturatedaqueous solution of ammonium chloride (300 mL), and concentrated invacuo to low volume. The aqueous residue is extracted with ethyl acetate(2×200 mL). The combined extracts are washed with brine (2×200 mL),dried over magnesium sulfate, and concentrated. The resulting residue issubjected to flash chromatography on silica gel, using a mixture ofethyl acetate and petroleum ether (b.p. 60-80° C.) (1:1 v/v), to give3-cyclopentylthio-N-(3,5-dichloropyrid-4-yl)-4-methoxybenzamide (2.5 g),in the form of a colorless solid, m.p. 198° C. [Elemental analysis:C,54.5,H,4.6; N,6.95; S,8.2%; calculated: C,54.4; H,4.6; N,7.05;S,8.1%].

EXAMPLE 27

Compound CH

By proceeding in the manner described in Example 26, but using theappropriate quantity of 3-isopropylthio-4-methoxybenzoyl chloride, thereis preparedN-(3,5-dichloropyrid-4-yl)-3-isopropylthio-4-methoxybenzamide, in theform of a white solid, m.p. 150-152° C. [Elemental analysis: C,52.1;H,4.4; N,7.5%; calculated: C,51.8,H,4.3; N,7.55%]

EXAMPLE 28

Compound CI

A solution ofN-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-(methylthio)benzamide (1g; that is prepared as described in Example 20) in dichloromethane (100mL), containing molecular sieve 4A, under nitrogen, is treated with2,6-di-tert-butyl-4-methylpyridine (1.28 g). The resulting mixture isstirred at room temperature for 1.5 hours, and then it is cooled to 0°C. (in an ice/salt bath) and treated with xenon difluoride (0.51 g) inone portion. After stirring for a further 2 hours in the cold, themixture is filtered, and the filtrate is washed with saturated aqueousammonium chloride solution. The organic phase is dried over sodiumsulfate and evaporated. The resulting residue is subjected to flashchromatography, eluting with a mixture of ethyl acetate and pentane (2:3v/v), to give impureN-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-(fluoromethylthio)-benzamide(600 mg). It is further purified by reversed phase HPLC onoctadecylsilyl silica gel, eluting with a mixture of methanol and water(7:3 v/v). to giveN-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-(fluoromethylthio)benzamide(519 mg), in the form of a white solid, m.p. 111-113° C. [Elementalanalysis: C,51.50; H,4.12; N,6.74%; calculated: C,52.05; H,4.12;N,6.74%].

EXAMPLE 29

Compound CJ

A suspension of chromium trioxide (0.6 g) in dichloromethane (25 mL) istreated with 3,5-dimethylpyrazole (0.58 g), and stirred for 20 minutes.It is then treated with a solution of1(3-cyclopentyloxy-4-methoxyphenyl)-2-(2,6-dichlorophenyl)ethanol (1.4g; that is prepared as described in Reference Example 61) indichloromethane (10 mL) and the solution is stirred overnight at roomtemperature. It is then concentrated and the resulting residue istriturated with diethyl ether (200 mL) and filtered. The filtrate isevaporated to give a brown oil, which is subjected to flashchromatography, eluting with a mixture of diethyl ether and pentane (1:4v/v), to give 3-cyclopentyloxy-4-methoxyphenyl 2',6'-dichlorobenzylketone (0.36 g), in the form of a white solid, m.p. 135-137° C.[NMR(CDCl₃): 7.73(dd,1H,J=8 Hz,J=2 Hz), 7.59(d,1H,J=Hz), 7.35(d,2H,J=8Hz),7.18(t,1H,J=8 Hz),6.94(d,1H,J=8 Hz),4.85(m,1H),4.66(s,2H),3.95(s,3H),2.05-1.52(m,8H). Elemental analysis:C,62.9,H,5.3%; calculated: C,63.3,H,5.3%].

EXAMPLE 30

Compound CK

A solution of oxalyl chloride (5.3 mL) in dry dichloromethane (125 mL)at -60° C. is treated portionwise with dimethyl sulfoxide (9.1 mL) indichloro-methane (20 mL), keeping the temperature below -50° C. Thesolution is then stirred at -70° C. for 20 minutes and is then treatedwith a suspension of1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(3,5-dichloropyrid-4-yl)ethanol(20.5 g; that is prepared as described in Reference Example 63) in drydichloro-methane (300 mL) during 20 minutes, keeping the temperaturebelow -50° C. After stirring for 30 minutes, the solution is treatedwith triethylamine (35 mL) and allowed to rise to room temperature. Itis then treated with water (250 mL) and extracted with ethyl acetate(2×100 mL). The combined organic extracts are washed with dilutesulfuric acid (100 mL; 1%), aqueous potassium carbonate solution (100ml; 5%) and brine (100 mL), dried and concentrated and the resultingresidue is recrystallized from a mixture of ethyl acetate and heptane,to give 3-cyclopentyloxy-4-methoxyphenyl 3,5-dichloropyrid-4-ylmethylketone (19.6 g), m.p. 119-120° C. [NMR(CDCl₃): 8.52(s,2H),7.69(dd,1H,J=8 Hz),7.57(d,1H,J=2 Hz),6.95(d,1H,J=8 Hz),4.86(m,1H),4.64(s,2H), 3.95(s,3H),2.05-1.58(m,8H). Elemental analysis:C,59.8,H,4.95,N,3.63%; calculated: C,60.0,H,5.0,N,3.7%].

EXAMPLE 31

Compound CL

Aqueous 27.5% hydrogen peroxide (0.32 mL) is added to a solution of3-cyclopentyloxy-4-methoxyphenyl 3,5-dichloropyrid-4-ylmethyl ketone(990 mg) in glacial acetic acid (13 mL). The reaction is heated at 80°C. for 8 hours then allowed to stand overnight at room temperature. Afurther aliquot of aqueous 27.5% hydrogen peroxide (0.32 mL) is addedand the mixture heated at 80° C. for 2 hours. The reaction mixture isdiluted with ethyl acetate (200 mL) and washed with saturated aqueoussodium bicarbonate until the washings remained basic. The mixture iswashed with brine (50 mL), dried (MgSO₄), concentrated and the residuerecrystallized from a mixture of dichloromethane/ethyl acetate/heptaneto give3,5-dichloro-4-(2-(3-cyclopentyloxy4-methoxyphenyl)-2-oxoethyl)pyridine-N-oxideas a yellow solid, m.p. 179-180° C. [Elemental analysis: C,57.3; H,4.81;N,3.54; Cl,18.0%; calculated for C₁₉ H₁₉ Cl₂ NO₄ : C,57.59; H,4.83;N,3.53; Cl,17.89%.].

EXAMPLE 32

Compound CM

A solution of diisopropylamine (1.23 mL) in dry tetrahydrofuran (15 mL)is stirred and cooled to -70° C. under a nitrogen atmosphere. To this isadded a 2.5 M solution of n-butyl lithium in hexanes (3.52 mL) at -70°C. The mixture is stirred for 30 minutes then a solution of3-chloro-4-methylpyridine (1.02 g) in dry tetrahydrofuran (10 mL) isadded. The mixture is stirred for a further 40 minutes. A solution of3-cyclopentyloxy-4,N-dimethoxy-N-methylbenzamide (2.23 g) in drytetrahydrofuran (10 mL) is added and the mixture stirred at -70° C. for30 minutes, -40° C. for 30 minutes, 0° C. for 30 minutes, and roomtemperature for 1 hour. A mixture of ethanol and hydrochloric acid 19:1(40 mL) is added and then the reaction mixture is partitioned betweenbrine (40 mL) and diethyl ether (40 mL). The ethereal phase is driedover sodium sulfate and concentrated in vacuo to give a pale yellowsolid (3.0 g). The solid is triturated with diethyl ether and thenpurified by flash chromatography (ethyl acetate eluent on a silicacolumn) to give a solid (1.6 g). The solid is triturated with diethylether, collected and dried to afford1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(3-chloropyrid-4-yl)ethanone(1.35 g) as a cream solid m.p. 124-125° C. [Elemental analysis: C,66.2;H,5.89; N,4.12%; calculated for C₁₉ H₂₀ ClNO₃ : C,65.99; H,5.83;N,4.05%.].

EXAMPLE 33

Compound CN

5% Palladium on carbon (53 mg) is added to a solution of3-cyclopentyloxy-4-methoxyphenyl 3,5-dichloropyrid-4-ylmethyl ketone(1.9 g) in hot methanol (60 mL) under a nitrogen atmosphere. The mixtureis brought to reflux, ammonium formate (1.6 g) is added portionwiseduring 10 minutes and then refluxing is continued for a further 45minutes. More 5% palladium on carbon (53 mg) and ammonium formate (1 g)are added and the mixture refluxed for 10 minutes. The reaction mixtureis partitioned between dichloromethane (250 mL) and water (100 mL). Theorganic phase is separated, washed with water (75 mL) and brine (100 mL)and dried over magnesium sulfate. Evaporation yields a yellow gum (1.3g) which is purified by flash chromatography (ethyl acetate/methanol19:1 v/v as eluent on a silica column) followed by recrystallizationfrom cyclohexane to give1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethanone (0.55 g) asan off-white solid, m.p. 102-103° C. [Elemental analysis: C,72.6;H,6.63; N,4.23%; calculated for C₁₉ H₂₁ NO₃ : C,73.29; H,6.80;N,4.50%.].

EXAMPLE 34

Compound CO

A solution of 3-cyclopentyloxy-4-methoxybenzonitrile (1.09 g) in drytetrahydrofuran (3 mL) is added to a 2 M solution of benzylmagnesiumchloride in tetrahydrofuran (5.0 mL) at room temperature under anitrogen atmosphere. The mixture is refluxed for 3 hours, cooled in anice bath and quenched with cold 4 M aqueous hydrochloric acid. Moretetrahydrofuran (20 mL) is added and the reaction mixture is allowed tostand at room temperature for 48 hours. The tetrahydrofuran layer isdecanted and evaporated. The residue is dissolved in cyclohexane (50 mL)and the solution washed successively with water (2×10 mL), 5% aqueoussodium bicarbonate (2×10 mL), water (2×10 mL) and brine (10 mL), andfinally dried over magnesium sulfate. Concentration affords an amber oil(1.53 g) which is purified by flash chromatography (dichloromethane aseluant on silica column) to give a pale yellow viscous oil whichcrystallized on standing. The solid is recrystallized from methanol toafford 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethanone ascolorless crystals, m.p. 117-119° C. [Elemental analysis: C,77.7;H,7.2%; calculated for C₂₀ H₂₂ O₃ : C,77.39; H,7.14%.].

EXAMPLE 35

Compound CP

By proceeding in a manner similar to that described in Example 51, butusing as the starting material the appropriate quantity of3-(3-methyl-2-butenyloxy)-4-methoxybenzoic acid, there is prepared3-(3-methyl-2-butenyloxy)-N-(3,5-dichloropyrid-4-yl)-4-methoxybenzamide,in the form of a white solid, m.p. 173-174° C. [Elemental analysis:C,56.7; H,4.9; N,7.3%; calculated: C,56.7; H,7.8; N,7.35%].

EXAMPLE 36

Compound CQ

By proceeding in a manner similar to that described in Reference Example47 (in the presence of a few drops of dimethylformamide) and Example 20,but using as the starting material the appropriate quantity of3-[exobicyclo-(2.2.1)hept-5-en-2-yloxy]-4-methoxybenzoic acid, there ispreparedN-(3,5-dichloropyrid-4-yl)-3-[exobicyclo(2.2.1)-hept-5-en-2-yloxy]-4-methoxybenzamide,in the form of white crystals, m.p. 175-176° C. [Elemental analysis:C,59.3; H,4.6; N,6.7; %; calculated: C,59.3; H,4.5; N,6.9%].

EXAMPLE 37

Compound CR

A stirred solution of 3-cyclopentyloxy-4-methoxyaniline (1 g) andtriethylamine (0.69 mL) in dry dichloromethane (20 mL) at 0° C. istreated dropwise with 2,6-dichlorobenzoyl chloride (1.17 g). Afterstirring at this temperature for 30 minutes, the mixture is warmed toroom temperature and stirred for a further 3 hours. The organic layer iswashed with water (100 mL), dried and concentrated. The residue isrecrystallized from a mixture of isopropanol and hexane, to giveN-(3-cyclopentyloxy-4-methoxyphenyl)-2,6-dichlorobenzamide (0.6 g), m.p.184-185° C. [Elemental analysis: C,60.2,H,5.0; N,3.6; Cl,18.9%;calculated: C,60.0; H,5.0; N,3.7; Cl,18.65%].

EXAMPLE 38

Compound CS

By proceeding in a similar manner to that described in Example 37, butusing 2,6-difluorobenzoyl chloride, there is preparedN-(3-cyclopentyloxy-4-methoxyphenyl)-2,6-difluorobenzarnide, m.p.150-151° C. [Elemental analysis: C,65.4; H,5.6; N,3.95; F,10.8%;calculated: C,65.7; H,5.5; N,4.0; F,10.9%].

EXAMPLE 39

Compound CT

A stirred solution of 3-cyclopentyloxy-4-methoxyaniline (1 g) andtriethylamine (0.69 mL) in dry dichloromethane (20 mL) is treateddropwise at 0-5° C. with a solution of 2,6-dichlorophenyl isocyanate(0.9 g) in dry dichloromethane (10 mL). The resulting mixture is stirredfor 30 minutes at this temperature and then for 6 hours at roomtemperature. The precipitate which forms is collected and stirred withisopropanol (50 mL), with ice cooling. The resulting solid is collectedand dried, to giveN-(2,6-dichlorophenyl)-N'-(3-cyclopentyloxy-4-methoxyphenyl)urea (1.06g), m.p. 203-204° C. [Elemental analysis: C,57.2; H,5.0; N,7.0;Cl,18.2%; calculated: C,57.7; H,5.1; N,7.1; Cl,18.0%].

EXAMPLE 40

Compound CU

A stirred solution of bis(trichloromethyl) carbonate (0.96 g) indichloromethane (10 mL) at room temperature is treated with a solutionof 3-cyclopentyloxy-4-methoxyaniline (2.0 g) in dichloromethane (10 mL)and then the mixture is stirred for a further 30 minutes during whichtime a thick precipitate forms. The mixture is diluted withdichloromethane, washed with water (50 mL), dried over magnesiumsulfate, and filtered. The solvent is removed in vacuo, to give a lightbrown oil, which is dissolved in dry tetrahydrofuran (10 mL) to give"solution A".

A stirred solution of 4-amino-3,5-dichloropyridine (1.56 g) in drytetrahydrofuran (20 mL) under nitrogen at room temperature is treatedportionwise with an oil dispersion of sodium hydride (60%; 0.37 g; 10mmol). After stirring for 15 minutes, the mixture is treated dropwisewith "solution A" and then stirred for a further 2 hours, during whichtime a thick cream precipitate forms. This is filtered off, washed withdiethyl ether (20 mL), and then with acetone (20 mL) and dried in vacuo.Recrystallization from methanol givesN-(3,5-dichloropyrid-4-yl)-N'-(3-cyclopentyloxy-4-methoxyphenyl)urea(0.68 g), m.p. 183-184° C. [Elemental analysis: C,54.4; H,4.8; N,10.4;Cl,17.7%; calculated: C,54.6; H,4.8; N,10.6; Cl,17.9%].

EXAMPLE 41

Compound CV

A stirred solution of 3-cyclopentyloxy-4-methoxyphenol (0.2 g) andtriethylamine (1.35 mL) in dichloromethane (5 mL) is treated portionwiseat 0-5° C. with 2,6-dichlorobenzoyl chloride (0.28 g), and the solutionis warmed to room temperature and stirred for a further 2 hours. Thereaction mixture is poured into hydrochloric acid (50 ml; 2 N) and isextracted with diethyl ether (3×50 mL). The combined organic extractsare then washed with water (100 mL), and brine (100 mL), dried overmagnesium sulfate and concentrated. The residual oil is subjected toflash chromatography on silica gel, eluting with a mixture of pentaneand ethyl acetate (4:1 v/v), to give (3-cyclopentyloxy-4-methoxyphenyl)2,6-dichlorobenzoate (0.28 g), m.p. 100-101° C. [Elemental analysis:C,59.7; H,4.7%; calculated: C,59.9; H,4.8%].

EXAMPLE 42

Compound CW

A stirred solution of 3-cyclopentyloxy-4-methoxyphenol (0.5 g),potassium carbonate (0.4 g) and alpha 2,6-trichlorotoluene (0.56 g) indimethylformamide (5 mL) is heated at 100° C. for 1 hour. The solutionis then concentrated and the residue is subjected to flashchromatography, eluting with a mixture of dichloromethane and pentane(1:1 v/v), to give 3-cyclopentyloxy-4-methoxyphenyl-2,6-dichlorobenzylether (0.76 g), m.p. 96-98° C. [Elemental analysis: C,61.7; H,5.5%;calculated: C,62.1; H,5.5%].

EXAMPLE 43

Compound CX

A solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (5 g) and2-chloroaniline (2.5 mL) in toluene (60 mL) is heated at reflux under aDean and Stark water trap for 3 hours. After concentration, the residueis dissolved in methanol (60 mL) and the stirred solution is treated at0° C. with sodium cyanoborohydride (2.1 g). The temperature is allowedto rise to room temperature, and the stirring is continued for 2 hours,before dilution with ethyl acetate (100 mL) and washing with saline (100mL). The organic layer is dried and concentrated, to give a brown oil.This oil is subjected to flash chromatography on silica gel, elutingwith a mixture of ethyl acetate and hexane (1:4v/v), to giveN-(2-chlorophenyl)-3-cyclopentyloxy-4-methoxybenzylamine (0.64 g), inthe form of an oil. [Elemental analysis: C,69.5; H,6.8; N,4.1; Cl,10.6%;calculated: C,68.8; H,6.7; N,3.2; Cl,10.7%].

EXAMPLE 44

Compound CY

A stirred suspension of 2,6-dichlorobenzyltriphenylphosphonium bromide(2.5 g) in dry tetrahydrofuran (30 mL) is treated dropwise with asolution of potassium t-butoxide (0.56 g) in dry tetrahydrofuran (32 mL)at 0° C. After stirring at this temperature for 1 hour, it is treatedwith a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (1.1 g) in drytetrahydrofuran (15 mL). The reaction mixture is stirred from 0° C. to5° C. for 1 hour and 30 minutes, and then allowed to warm to roomtemperature. After stirring overnight, the mixture is concentrated andthe resulting residue is treated with ethyl acetate (200 mL). Theresulting organic solution is filtered. The filtrate is concentrated andthe resulting residue is subjected to flash chromatography, eluting withdichloromethane, to givetrans-1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(2,6-dichlorophenyl)ethene(1.16 g), m.p. 47-49° C. [Elemental analysis: C,66.4; H,5.6; Cl,19.4%,calculated: C,66.1; H,5.55; Cl,19.5%].

EXAMPLE 45

Compound CZ

By proceeding in a manner similar to that described in Example 44, butusing 2,6-difluorobenzyltriphenylphosphonium bromide, there is preparedtrans-1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(2,6-difluorophenyl)ethene,m.p. 65-67° C. [Elemental analysis: C,73.0; H,6.1%; calculated: C,72.7;H,6.1%].

EXAMPLE 46

Compound DA

Pyridinium dichromate (3.6 g) in dry dichloromethane (40 mL) undernitrogen is treated with(±)-1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(pyrid-4-yl)ethanol (2.0 g;that is prepared as described in Reference Example 67), in one portion.The resulting mixture is stirred for 1 hour and 30 minutes, and thenfiltered through a pad of diatomaceous earth, and the pad is washed withdiethyl ether. The combined filtrate and ethereal washings are washedwith saturated aqueous cupric sulfate solution (2×30 mL), followed bywater (30 mL), and then dried over magnesium sulfate. The solvent isremoved under reduced pressure, and the resulting oily residue issubjected to flash chromatography on silica gel, eluting with ethylacetate, to give1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(pyrid-4-yl)ethane-1,2-dione (0.4g), in the form of a yellow solid, m.p. 117-119° C. [Elemental analysis:C,70.1; H,6.0; N,4.1%; calculated: C,70.1; H,5.9; N,4.3%].

EXAMPLE 47

Compound DB

A stirred solution of diisopropylamine (3.6 mL) in dry tetrahydrofuran(132 mL) is treated with a solution of butyl lithium in hexanes (10.3mL; 2.5 M), dropwise, under nitrogen, keeping the temperature below -65°C. The resulting mixture is then stirred for a further period of 20minutes, at below -65° C. The stirred mixture, still maintained at below-65° C., is then treated dropwise with a solution of3,5-dichloropyridine (3.5 g) in dry tetrahydrofuran (24 mL). The stirredmixture is maintained at below -65° C. for a further 30 minutes. Thestirred mixture, still maintained at below -65° C., is then treatedportionwise with 3-cyclopentyloxy-4-methoxyphenyldiazoniumtetrafluoroborate (7.2 g), and it is stirred at below -65° C. for afurther 45 minutes. The resulting mixture is then allowed to warm toroom temperature overnight. It is then treated with water (600 mL), thelayers are separated, and the aqueous layer is further extracted withdiethyl ether (3×100 mL). The combined organic extracts are washed withsaturated aqueous sodium chloride solution (100 mL), dried overmagnesium sulfate, and then evaporated to dryness. The resulting residueis subjected to flash chromatography on silica gel, eluting with amixture of pentane and diethyl ether (2:1 v/v), to give a red solid (3.1g) which, on recrystallization from pentane, givestrans-1-(3-cyclopentyloxy-4-methoxyphenyl)2-(3,5-dichloropyrid-4-yl)diazene(2.2 g), in the form of a red-brown solid, m.p. 88-89° C. [Elementalanalysis: C,56.0; H,4.8; N,11.3%; calculated: C,55.75; H,4.7; N,l 1.5%].

EXAMPLE 48

Compounds DC and DD

A solution oftrans-1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(3,5-dichloropyrid-4-yl)diazene(1.2 g; that is prepared as described in Example 47) in dichloromethane(24 mL) is treated portionwise with metachloroperbenzoic acid (0.6 g).The resulting mixture is stirred in the dark for 2 hours and 30 minutes,and then it is allowed to stand in the dark overnight. After theaddition of a further quantity of dichloromethane (24 mL), the mixtureis shaken with saturated aqueous sodium bicarbonate solution (12 mL).The layers are separated and the aqueous phase is further extracted withdichloromethane (3×6 mL). The combined organic extracts are washed withsaturated aqueous sodium carbonate solution (6 mL), dried over magnesiumsulfate, and evaporated to dryness. The resulting residual gum isdissolved in a mixture of dichloromethane and diisopropyl ether (1:2v/v), and treated with activated carbon. After filtration, the solutionis concentrated to low bulk. The resulting crystalline solid is filteredoff and washed with diisopropyl ether and pentane, and dried in air.This material (0.71 g) is subjected to flash chromatography on silicagel, eluting initially with dichloromethane, and then with a mixture ofdichloromethane and methanol (19:1 v/v), to give a solid (0.58 g), whichis purified by reverse phase high pressure liquid chromatography onoctadecylsilyl silica gel, eluting with a mixture of methanol and water(3:1 v/v).

1-(3-Cyclopentyloxy-4-methoxyphenyl)-c-1-oxo-r-2-(3,5-dichloro-1-oxopyrid-4-yl)diazene(0.17 g) is eluted first in the form of a yellow solid, m.p. 139-141° C.[Elemental analysis: C,51.4; H,4.4; N,10.4%; calculated: C,51.3; H,4.3;N,10.6%].

Trans-1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(3,5-dichloro-1-oxopyrid-4-yl)diazene(0.31 g) is eluted second, in the form of a red solid, m.p. 172-174° C.[Elemental analysis: C,53.4; H,4.5; N,10.9%; calculated: C,53.4; H,4.5;N,11.0%].

EXAMPLE 49

Compound DE

A stirred solution ofN-(3-hydroxy-4-methoxyphenylsulfonyl)-2-chloroaniline, containing someN,N-bis(3-hydroxy-4-methoxyphenyl-sulfonyl)-2-chloroaniline (0.7 g; thatis prepared as described in Reference Example 72) in dimethylformamide(20 mL) is treated portionwise with an oil dispersion of sodium hydride(60%; 0.11 g, 2.7 mmol) and the mixture is stirred at 60° C. for 1 hour.It is then treated dropwise with cyclopentyl bromide (0.32 mL) and thesolution is stirred at 60° C. for a further period of 4 hours. Aftercooling, the mixture is treated with water (20 mL) and extracted withdiethyl ether (2×75 mL). The organic extracts are combined, dried andevaporated, to give an oil which is subjected to flash chromatography onsilica gel, eluting with diethyl ether, to giveN-(2-chlorophenyl)-3-cyclopentyloxy-4-methoxybenzenesulfonamide (150mg), m.p. 113-115° C. [NMR(CDCl₃): 7.68(dd,1H,J=8 Hz,J=2Hz),7.37(dd,1H,J=8 Hz,J=2 Hz), 7.26(d,1H, J=2 Hz), 7.24(dt,1H,J=8 Hz,J=2Hz),7.13(d,1H,J=2 Hz),7.04(dt,1H, J=8 Hz,J=2 Hz),6.92(bs,1H),6.82(d,1H,J=8 Hz),4.65(m,1H), 3.86(s,3H),1.92-1.55 (m,8H)].

EXAMPLE 50

Compound DO

Sodium hydride (0.14 g) is added to a solution of3,5-dichloro-4-aminopyridine (0.28 g) in dimethylformamide (7 mL) undernitrogen and the mixture is stirred at room temperature for 15 minutes.A solution of 3-cyclopentyloxy-4-trifluoromethoxybenzoyl chloride (0.54g) in dimethylformamide (3 mL) is then added dropwise and the mixture isstirred at room temperature for 3 hours. Water (50 mL) is added and themixture is extracted with ethyl acetate (2×75 mL). The combined extractsare dried over magnesium sulfate and evaporated under reduced pressure,to give a brown oil, which is subjected to mplc, eluting with a mixtureof diethyl ether and pentane (3:7 v/v), to giveN-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-trifluoro-methoxybenzamide(0.6 g), in the form of a white solid. m.p. 129-131° C., Elementalanalysis: C,50.0; H,3.5; N,6.6; Cl,16.3%; calculated: C,49.7; H,3.5;N,6.4; Cl,16.2%].

EXAMPLE 51

Compound DP

A stirred solution of3-(4,4-difluoro-3-methylenecyclobut-1-enyloxy)-4-methoxybenzoic acid(0.7 g) in acetone (24 mL) is treated with triethylamine (0.4 mL) andcyanuric chloride (0.24 g) and the solution is stirred for 4 hours atroom temperature. The precipitated solid is filtered off and thefiltrate is evaporated to dryness in vacuo. The residue is treated withdry tetrahydrofuran (12 mL) and filtered, to give "solution A",containing3-(4,4-difluoro-3-methylenecyclobut-1-enyloxy)-4-methoxy-benzoylchloride.

A stirred solution of 3,5-dichloro-4-aminopyridine (0.42 g) in drytetrahydrofuran (24 mL) at room temperature is treated with sodiumhydride (60% dispersion in oil; 0.21 g), portionwise, under nitrogen andstirred for 2 hours. It is then treated, dropwise, with "solution A" andstirred at room temperature for 3 hours. The reaction mixture is dilutedwith water (100 mL) and extracted with ethyl acetate (2×50 mL). Theextract is washed with water, dried over magnesium sulfate andconcentrated. The residue is subjected to flash chromatography, elutingwith a mixture of diethyl ether and pentane (1:1 v/v), to giveN-(3,5-dichloropyrid-4-yl)-3-(4,4-difluoro-3-methylenecyclobut-1-enyloxy)-4-methoxybenzamide(0.44 g), m.p. 102-104° C. [Elemental analysis: C,52.4; H,3.15; Cl,16.8;N,6.7%; calculated: C,52.3; H,2.9; Cl,16.8; N,6.7%].

EXAMPLE 52

Compound DQ

By proceeding as described in Example 25, but using the appropriatequantities of 3-isopropoxy-4-difluoromethoxybenzoic acid and4-amino-3,5-difluoropyridine, there is preparedN-(3,5-difluoropyrid-4-yl)-3-isopropoxy-4-difluoromethoxybenzamide, inthe form of a white solid, m.p. 101-103° C., [Elemental analysis:C,53.7; H,4.0; N,7.7%; calculated: C,53.6; H,3.9; N,7.8%].

EXAMPLE 53

Compound DR

By proceeding as described in Example 9, but using the appropriatequantity ofN-(3,5-difluoropyrid-4-yl)-3-isopropoxy-4-difluoromethoxy-benzamide,there is preparedN-(3,5-difluoro-1-oxido-4-pyridinio)-3-isopropoxy-4-difluoromethoxybenzamidein the form of a white solid, m.p. 55° C., [Elemental analysis: C,50.2;H,3.7; N,7.5%; calculated (for a form containing 0.5 molecules of waterper molecule): C,50.1; H,4.0; N,7.3%].

EXAMPLE 54

Compound DS

By proceeding as described in Reference Example 3 and Example 25, butusing the appropriate quantities of3-isopropoxy-4-difluoromethoxybenzoic acid and4-amino-3,5-dichloropyridine, there is preparedN-(3,5-dichloro-pyrid-4-yl)-3-isopropoxy-4-difluoromethoxybenzamide, inthe form of a white solid, m.p. 113-114° C., [Elemental analysis:C,49.3; H,3.7; N,7.1%; calculated: C,49.1; H,3.6; N,7.1%].

EXAMPLE 55

Compound DT

By proceeding as described in Example 9, but using the appropriatequantity ofN-(3,5-dichloropyrid-4-yl)-3-isopropoxy-4-difluoromethoxy-benzamide,there is preparedN-(3,5-dichloro-1-oxido-4-pyridinio)-3-isopropoxy-4-difluoromethoxybenzamide,in the form of a white solid, m.p. 138-140° C., [Elemental analysis:C,46.1; H,3.7; Cl,17.0; N,6.8%; calculated (for a form containing 0.5molecules of water per molecule): C,46.2; H1,3.6; Cl,17.0; N,6.7%].

EXAMPLE 56

Compound DU

By proceeding as described in Example 25, but using the appropriatequantity of 3-(exo)-8,9,10-trinorborn-2-yloxy-4-difluoro-methoxybenzoicacid, there is prepareddichloro-4-pyridyl)-4-difluoromethoxy-3-(exo)-8,9,10-trinorborn-2-yloxybenzamidein the form of a white solid, m.p. 152-154° C., [Elemental analysis:C,54.4; H,4.1; N,6.3%; calculated: C,54.2; H,4.1; N,6.3%].

EXAMPLE 57

Compound DV

By proceeding as described in Example 9, but using the appropriatequantity ofN-(3,5-dichloro-4-pyridyl)-4-difluoromethoxy-3-(exo)-8,9,10-tri-norborn-2-yloxybenzamide,there is preparedN-(3,5-dichloro-1-oxido-4-pyridinio)-4-difluoromethoxy-3-(exo)-8,9,10-trinorborn-2-yloxybenzamide,m.p. 101-103° C.

EXAMPLE 58

Compound DW

A suspension of 3-(2-fluorocyclopentyloxy)-4-methoxybenzoic acid (0.48g) in toluene (20 mL) is treated with thionyl chloride (0.34 g) and thenis heated at 60° C. for 3 hours, and cooled and evaporated to give3-(2-fluorocyclopentyl-oxy)-4-methoxybenzoyl chloride.

A suspension of sodium hydride (0.3; 60% oil dispersion) indimethylformamide (5 mL) is treated with 4-amino-3,5-dichloropyridine(0.62 g) and the mixture is stirred for 40 minutes. A solution of3-(2-fluoro-cyclopentyloxy)-4-methoxybenzoyl chloride indimethylformamide (12 mL) is added, and the mixture is stirred at 80-90°C. for 1 day. The solution is cooled, poured into water (75 mL) andextracted with dichloromethane (3×50 mL). The combined organic extractsare washed with brine (50 mL), dried over magnesium sulfate andconcentrated. The residue is subjected to flash chromatography, elutingwith a mixture of ethyl acetate and petroleum ether (1:3 v/v), to giveN-(3,5-dichloropyrid-4-yl)-3-(2-fluorocyclopentyloxy)-4-methoxybenzamide(0.26 g), m.p. 167-169° C. [Elemental analysis: C,53.8; H,4.2; N,6.75;Cl,17.8%; calculated: C,54.15; H,4.3; N,7.0; Cl,17.8%].

EXAMPLE 59

Compound DX

By proceeding in a similar manner as in Example 58, but using theappropriate quantity of 3-(tetrahydrothiophen-3-oxy)-4-methoxybenzoicacid, there is preparedN-(3,5-dichloro-pyrid-4-yl)-3-(tetrahydrothiophen-3-oxy)-4-methoxybenzamide,in the form of a white solid, m.p. 160-162° C., [Elemental analysis:C,51.1; H,4.0; Cl,17.6; N,7.2%; calculated: C,51.1; H,4.0; Cl,17.8;N,7.0%].

EXAMPLE 60

Compound DY

By proceeding in a similar manner to Example 9, but using3-cyclopentyloxy-N-(3,5-dichloropyrid-4-yl)-4-difluoromethoxy-benzamideas the starting material, there is prepared3-cyclopentyloxy-N-(3,5-dichloro-1-oxido-4-pyridinio)-4-difluoromethoxybenzamide,in the form of a white solid (m.p. 119-121° C.).

EXAMPLE 61

Compound DZ

By proceeding in a manner similar to that described in Example 20, butusing as the starting material the appropriate quantity of3-isopropoxy-4-(methylthio)benzoyl chloride, there is preparedN-(3,5-dichloropyrid-4-yl)-3-isopropoxy-4-(methylthio)benzamide, in theform of a white solid, m.p. 146-148° C. [Elemental analysis: C,51.9;H,4.5; N,7.4; Cl,18.8; S,8.5%; calculated: C,51.7; H,4.3; N,7.5;Cl,19.0%].

EXAMPLE 62

Compound EA

By proceeding in a manner similar to that described in Example 20, butusing as the starting material the appropriate quantities of3-isopropoxy-4-(methylthio)benzoyl chloride and4-amino-3,5-difluoropyridine, there is preparedN-(3,5-difluoropyrid-4-yl)-3-isopropoxy-4-(methylthio)benzamide, in theform of a white solid, m.p. 175-177° C. [Elemental analysis: C,56.6;H,4.8; N,8.2; S,9.7%; calculated: C,56.8; H,4.8; N,8.3; S,9.5%].

EXAMPLE 63

Compound EB

By proceeding in a manner similar to that described in Example 20, butusing as the starting material the appropriate quantity of3-(pent-3-yloxy)-4-(methylthio)benzoyl chloride, there is preparedN-(3,5-dichloropyrid-4-yl)-3-(pent-3-yloxy)-4-(methylthio) benzamide, inthe form of a white solid, m.p. 154-155° C. [Elemental analysis: C,53.8;H,4.9; N,7.0; S,7.8%; calculated: C,54.14; H,5.05; N,7.0; S,8.0%].

EXAMPLE 64

Compound EC

By proceeding in a manner similar to that described in Example 30, butusing as the starting material the appropriate quantity ofrac-1-[3-{(exo)-8,9,10-trinorbornyl-2-oxy}-4-methoxyphenyl]-2-(3,5-dichloropyrid-4-yl)ethanolthere is prepared, after flash chromatography, eluting with a mixture ofethyl acetate and pentane (1:2 v/v),(±)-1-[3-{(exo)-8,9,10-trinorbornyl-2-oxy}-4-methoxyphenyl]-2-(3,5-dichloropyrid-4-theform of a white solid, m.p. 113-114° C. [Elemental analysis: C,61.9;H,5.2; N,3.4%; calculated: C,62.1; H,5.2; N,3.4%].

EXAMPLE 65

Compound ED

By proceeding in a manner similar to that described in Example 30, butusing as the starting material the appropriate quantity of1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(3,5-dichloropyrid-4-yl)ethanol,there is prepared1-[3-cyclopentyloxy-4-(methylthio)phenyl]-2-(3,5-dichloropyrid-4-yl)ethanonein the form of a yellow solid, m.p 110-111° C. [Elemental analysis:C,57.6; H,4.8; Cl,17.8; N,3.4; %; calculated: C,57.6; H,4.8; Cl,17.9;N,3.5%].

EXAMPLE 66

Compound EE

By proceeding in a manner similar to that described in Example 30, butusing as the starting material the appropriate quantity of1-(4-methoxy-3-prop-2-yloxyphenyl)-2-(3,5-dichloropyrid-4-yl)ethanol,there is prepared1-(4-methoxy-3-prop-2-yloxyphenyl)-2-(3,5-dichloropyrid-4-yl)ethanone,in the form of a buff solid, m.p. 153-155° C. [Elemental analysis:C,56.9; H,4.83; N,3.85%; calculated:57.64; H, 4.84; N,3.95%].

EXAMPLE 67

Compound EF

By proceeding in a manner similar to that described in Example 30, butusing as the starting material the appropriate quantity of1-(4-methylthio-3-prop-2-yloxyphenyl)-2-(3,5-dichloropyrid-4-yl)ethanol,there is prepared1-(4-methylthio-3-prop-2-yloxyphenyl)-2-(3,5-dichloropyrid-4-yl)ethanone,in the form of a white solid, m.p. 116-117° C. [Elemental analysis:C,55.0; H,4.59; Cl,19.1; N,3.68; S,8.6%; calculated: C,55.14; H,4.63;Cl,19.2; N,3.78; S,8.7%].

EXAMPLE 68

Compound EG

Hydrogen peroxide (8 mL) is added to a stirred suspension of1-(4-methoxy-3-prop-2-yloxyphenyl)-2-(3,5-dichloropyrid-4-yl)ethanone(5.97 g) in glacial acetic acid (17 mL). The mixture is stirred at70-80° C. for 3 hours. After cooling, the mixture is basified bytreatment with aqueous sodium hydroxide (6 M), and extracted with ethylacetate. The extracts are washed with brine, dried over magnesiumsulfate and evaporated, to give a white solid which is triturated withpentane and dried at 80° C., to give1-(4-methoxy-3-prop-2-yloxyphenyl)-2-(3,5-dichloro-1-oxido-4-pyridinio)ethanone,in the form of a white solid, m.p. 167-169° C. [Elemental analysis:C,55.4; H,4.61; Cl,19.3; N,3.72%, calculated: C,55.15; H,4.63; Cl,19.2;N,3.78%].

EXAMPLE 69

Compound EH

By proceeding in a manner similar to that described in Example 30, butusing as the starting material the appropriate quantity of1-(3-cyclopentyloxy-4-difluoromethoxyphenyl)-2-(3,5-dichloropyrid-4-yl)-ethanol,there is prepared1-(3-cyclopentyloxy-4-difluoromethoxyphenyl)-2-(3,5-dichloropyrid-4-yl)ethanone,in the form of a white solid, m.p. 80-82° C. [Elemental analysis:C,55.1; H,4.1; N,3.2%; calculated: C,54.8; H,4.1; N,3.4%].

EXAMPLE 70

Compound EI

By proceeding in a manner similar to that described in Example 9, butusing as the starting material the appropriate quantity of1-(3-cyclopentyloxy-4-difluoromethoxyphenyl)-2-(3,5-dichloropyrid-4-yl)ethanone,there is prepared1-(3-cyclopentyloxy-4-difluoromethoxy-phenyl)-2-(3,5-dichloro-1-oxido-4-pyridinio)ethanone,in the form of a white solid, m.p. 178-179° C. [Elemental analysis:C,53.1; H,4.1; N,3.1%; calculated: C,52.8; H,4.0; N,3.2%].

EXAMPLE 71

Compound EJ

By proceeding in a manner similar to that described in Example 30, butusing as the starting material the appropriate quantity of2-(3,5-dichloro-pyrid-4-yl)-1-[3-{exobicyclo(2.2.1)hept-5-en-2-yloxy}-4-methoxyphenyl]ethanol,there is prepared2-(3,5-dichloropyrid-4-yl)-1-[3-{exobicyclo(2.2.1)hept-5-en-2-yloxy}-4-methoxyphenyl]ethanone,in the form of a white solid, m.p. 89-91° C. [Elemental analysis:C,62.6; H,4.75; N,3.4%; calculated: C,62.4; H,4.7; N,3.5%].

EXAMPLE 72

Compound EK

By proceeding in a manner similar to that described in Example 30, butusing as the starting material the appropriate quantity of2-(3,5-dichloro-4-pyridyl)-1-[4-difluoromethoxy-3-(exo)-8,9,10-trinorborn-2-yloxyphenyl]ethanol,there is prepared2-(3,5-dichloro-4-pyridyl)-1-(4-difluoromethoxy-3-(exo)-8,9,10-trinorborn-2-yloxyphenyl)ethanone,in the form of a white solid, m.p. 120-122° C.

EXAMPLE 73

Compound EL

By proceeding in a manner similar to that described in Example 9, butusing as the starting material the appropriate quantity of2-(3,5-dichloro-4-pyridyl)-1-[4-difluoromethoxy-3-(exo)-8,9,10-trinorborn-2-yloxyphenyl]ethanol,there is prepared2-(3,5-dichloro-1-oxido-4-pyridinio)-1-[4-difluoromethoxy-3-(exo)-8,9,10-trinorborn-2-yloxyphenyl]ethanone,in the form of a white solid, m.p. 59-61° C.

EXAMPLE 74

Compound EM

By proceeding in a manner similar to that described in Example 30, butusing as the starting material the appropriate quantity of2-(3,5-dichloro-4-pyridyl)-1-[4-methoxy-3-(3-methyl-2-butenyloxy)-phenyl]ethanol,there is prepared2-(3,5-dichloro-4-pyridyl)-1-[4-methoxy-3-(3-methyl-2-butenyloxy)-phenyl]ethanone,in the form of a white solid. m.p. 115-117° C.

EXAMPLE 75

Compound EN

By proceeding in a manner similar to that described in Example 30, butusing as the starting material the appropriate quantity of2-(3,5-dichloro-4-pyridyl)-1-(4-difluoromethoxy-3-isopropoxyphenyl)-ethanol.there is prepared2-(3,5-dichloro-4-pyridyl)-1-(4-difluoromethoxy-3-isopropoxyphenyl)ethanonein the form of a white solid, m.p. 85-87° C. [Elemental analysis:C,52.7; H,3.85; N,3.6%; calculated: C,52.3; H,3.9; N,3.6%].

EXAMPLE 76

Compound EO

By proceeding in a manner similar to that described in Example 9, butusing as the starting material the appropriate quantity of2-(3,5-dichloro-4-pyridyl)-1-(4-difluoromethoxy-3-isopropoxyphenyl)-ethanonethere is prepared2-(3,5-dichloro-1-oxido-4-pyridinio)-1-(4-difluoromethoxy-3-isopropoxyphenyl)-ethanone,in the form of a white solid, m.p. 138-140° C. [Elemental analysis:C,50.3; H,3.7; N,3.2; Cl,17.6%; calculated: C,50.2; H,3.7; N,3.45;Cl,17.45%].

EXAMPLE 77

Compound EP

By proceeding in a manner similar to that described in Example 42, butusing as the starting material the appropriate quantity of4-bromomethyl-3,5-dichloropyridine, there is prepared3,5-dichloro-4-(3-cyclopentyloxy-4-methoxyphenoxymethyl)pyridine, in theform of a white solid, m.p. 75-77° C.

EXAMPLE 78

Compound EQ

By proceeding in a manner similar to that described in Example 9, butusing as the starting material the appropriate quantity ofN-(3,5-dichloro-pyrid-4-yl)-3-(exo)-8,9,10-trinorborn-2-yloxybenzamide,there is preparedN-(3,5-dichloro-1-oxido-4-pyridinio-4-methoxy-3-(exo)-8,9,10-trinorborn-2-yloxy-benzamide,m.p. 130-132° C.

REFERENCE EXAMPLE 1

A stirred solution of 3-hydroxy-4-methoxybenzaldehyde (2.00 g) in drydimethylformamide (20 mL) is treated portionwise with sodium hydride(60% dispersion in oil; 0.56 g) and the mixture is then heated for 1hour at 50° C. It is then treated dropwise with cyclopentyl bromide(2.36 g) and is stirred and heated at 50° C. for 22 hours. The solutionis diluted with water (100 mL) and extracted with diethyl ether (2×100mL). The ethereal extracts are combined, dried over magnesium sulfateand concentrated, to give 3-cyclopentyloxy-4-methoxybenzaldehyde (1.65g) in the form of a golden oil.

By proceeding in a similar manner, but using the appropriate quantitiesof cyclohexyl bromide, butyl bromide and propyl bromide, respectively,there are prepared:

3-cyclohexyloxy-4-methoxybenzaldehyde in the form of a golden oil[Elemental analysis: C,71.8; H,7.8%; Calculated: C,71.8; H,7.7%];

3-butoxy-4-methoxybenzaldehyde in the form of a light brown oil[NMR(CDCl₃): 1.0(t,3H),1.5(m,2H),1.9(m,2H),3.96(s,3H),4.1(t,2H),6.96(d,1H),7.4(m,2H),9.8(s,1H)]; and

3-propoxy-4-methoxybenzaldehyde [NMR(CDCl₃):9.85(s,1H),7.4(dd,1H),7.4(d,1H), 7.0(d,1H),4.05(t,2H),4.0(s,3H),1.9(m,2H),1.06(t,3H)].

REFERENCE EXAMPLE 2

A stirred saturated aqueous solution of potassium permanganate (100 mL)is treated with 3-cyclopentyloxy-4-methoxybenzaldehyde (7.4 g; that isprepared as described hereinbefore in Reference Example 1) and sodiumcarbonate (3.4 g) and the mixture is stirred at 50° C. for 1 hour, andthen cooled to room temperature. The reaction mixture is acidified bytreatment with concentrated hydrochloric acid and then it is treatedwith aqueous sodium bisulfite solution until a colorless solution isobtained. The reaction mixture is extracted with dichloromethane (2×100mL) and the organic extracts are dried over magnesium sulfate andconcentrated. The resulting residue is recrystallized from diethylether, to give 3-cyclopentyloxy-4-methoxybenzoic acid (4.78 g) in theform of white crystals. [NMR(CDCl₃): 1.7(s,2H),1.8-2.2(m,6H),3.95(s,3H),4.85(s,1H),6.9(bs,1H)7.6(bs,1H), 7.8(s,1H),9.8(s,1H);Elemental analysis: C,65.6; H,6.8%; Calculated: C,66.1; H,6.8%].

By proceeding in a similar manner, but using the appropriate quantitiesof the corresponding benzaldehyde derivatives, prepared as describedhereinbefore in Reference Example 1, there are prepared:

3-cyclohexyloxy-4-methoxybenzoic acid in the form of a white solid, m.p.158-160° C. [NMR(CDCl₃): 1.2-2.1 (m,10H),3.94(s,3H),4.3(m,1H),6.9(d,1H),7.6(s,1H), 7.75 (d,1H)];

3-butoxy-4-methoxybenzoic acid in the form of a white solid, m.p.130-132° C. [NMR(CDCl₃): 1.0 (t,3H), 1.5 (m,2H),1.85(m,2H),3.95(s,3H),4.1(t,2H),6.92(d,2H),7.6 (s,1H),7.75(d,1H)]; and

3-propoxy-4-methoxybenzoic acid [(NMR(CDCl₃): 7.76(dd,1H),7.6(d,1H),6.9(d,1H),4.04(t,2H),3.94(s,3H),1.9(m,2H),1.05(t,3H)].

REFERENCE EXAMPLE 3

Stirring thionyl chloride (20 mL) is treated portionwise with3-cyclopentyloxy-4-methoxybenzoic acid (5.0 g; that is prepared asdescribed hereinbefore in Reference Example 2) and the solution is thenheated at 85° C. for 3 hours. Toluene (50 mL) is added and the mixtureis concentrated to give 3-cyclopentyloxy-4-methoxybenzoyl chloride (4.12g) in the form of an oil which slowly crystallized. [NMR(CDCl₃): 1.6-1.7(m,2H),1.8-1.95(m,4H),1.94-2.05(m,2H),3.94(s,3H),4.85(m,1H),6.9(d,1H),7.55(d,1H),7.8(q,1H); Elemental analysis: C,61.3;H,5.94; Cl,13.9%; Calculated: C,61.3; H,5.94; Cl,13.92%].

By proceeding in a similar manner, but using the appropriate quantitiesof the corresponding benzoic acid derivatives, that are prepared asdescribed hereinbefore in Reference Example 2, there are prepared:

3-cyclohexyloxy-4-methoxybenzoyl chloride in the form of a colorlesssolid;

3-butoxy-4-methoxybenzoyl chloride in the form of a light brown oil; and

3-propoxy-4-methoxybenzoyl chloride [(NMR(CDCl₃): 7.82(dd,1H),7.53(d,1H), 6.92(d,1H),4.03(t,2H),3.96(s,3H),1.89(m,2H),1.06(t,3H)].

REFERENCE EXAMPLE 4

A stirred solution of 4-aminopyridine (40 g) in concentratedhydrochloric acid (500 mL) at 80° C. is treated dropwise with aqueoushydrogen peroxide solution (200 mL; 15% w/w), while keeping thetemperature between 80° C. and 85° C. The solution is then cooled andbasified by dropwise treatment with aqueous sodium hydroxide solution(50% w/w), while keeping the temperature below 15° C. The resultingwhite flocculent precipitate is recrystallized from toluene, to give4-amino-3,5-dichloropyridine (61.5 g), m.p. 161.5-162.5° C.

REFERENCE EXAMPLE 5

A solution of 4-aminopyridine (47 g) in concentrated hydrochloric acid(355 mL) is treated portionwise at 80° C. with an aqueous solution ofsodium hypochlorite (550 mL; 15% w/v). The mixture is cooled to 30° C.and basified by treatment with aqueous sodium hydroxide solution (300mL; 35% w/v) during 20 minutes. The mixture is stirred and cooled for afurther 30 minutes and then it is filtered. The solid is washed wellwith water and dried at 60° C. to give 4-amino-3,5-dichloropyridine(69.5 g).

REFERENCE EXAMPLE 6

A solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (66 g) and sulfamicacid (39.6 g) in glacial acetic acid (500 mL) is treated dropwise during1 hour with a solution of sodium chlorite (35 g) in water (150 mL). Themixture is stirred at 20° C. during 1 hour and then it is treated withwater (500 mL) dropwise during 30 minutes. The resulting solid isfiltered, washed with water and dried, to give3-cyclopentyloxy-4-methoxybenzoic acid (60.9 g) in the form of whitecrystals [Elemental analysis: C,65.8; H,6.7%; calculated: C,66.1;H,6.8%].

REFERENCE EXAMPLE 7

A solution of triphenylphosphine (17.5 g) in dry tetrahydrofuran (50 mL)under nitrogen is treated with a solution of diisopropylazodicarboxylate (13.5 g) in dry tetrahydrofuran (50 mL). The solutionis stirred is treated with a solution of endo-8,9,10-trinorborneol (5.0g) in dry tetrahydrofuran (50 mL) followed by a solution of3-hydroxy-4-methoxybenzaldehyde (10.2 g) in dry tetrahydrofuran (50 mL).The solution is heated at reflux for 15 hours, cooled, poured into water(600 mL), and extracted with diethyl ether (300 mL). The extract iswashed with water (100 mL), with aqueous sodium hydroxide solution(2×100 mL; 1 M) and with water (2×100 mL), dried over magnesium sulfateand evaporated, to give an oil, which is subjected to flashchromatography on silica gel, eluting with a mixture of pentane andethyl acetate (95:5 v/v) to give3-(exo-8,9,10-trinorbornyl-2-oxy)-4-methoxybenzaldehyde (8.2 g), m.p.56-61° C.

REFERENCE EXAMPLE 8

A stirred suspension of 3-hydroxy-4-methoxybenzaldehyde (50 g) in water(200 mL) at between 0 and 5° C. is treated dropwise with an aqueoussolution of sodium hydroxide (200 mL; 20% w/v), followed at between 0and 5° C. by benzoyl chloride (38 mL). The reaction mixture is stirredat between 0 and 5° C. for 1 hour and then it is allowed to warm to roomtemperature and is stirred for a further period of 2 hours. Theresulting solution is extracted with dichloromethane (2×200 mL) and thecombined extract is washed with water (200 mL), dried over magnesiumsulfate and concentrated, to give 2-methoxy-5-formylphenyl benzoate(35.2 g), m.p. 70-72° C.

REFERENCE EXAMPLE 9

A stirred solution of potassium permanganate (28 g) in acetone (200 mL)is treated with 2-methoxy-5-formylphenyl benzoate (35.2 g; that isprepared as described in Reference Example 8), and the resultingvigorously reacting mixture is cooled in an ice bath. It is then stirredat room temperature for 3 hours. The mixture is then concentrated andthe residue is treated with saturated aqueous sodium metabisulfitesolution (300 mL). The resulting white solid is filtered off, washedwell with water (200 mL), and dried, to give3-benzoyloxy-4-methoxy-benzoic acid (29.3 g), m.p. 180-183° C.

REFERENCE EXAMPLE 10

A solution of 3-benzoyloxy-4-methoxybenzoic acid (29.3 g; that isprepared as described in Reference Example 9) in toluene (300 mL) istreated with thionyl chloride (30 mL) and heated on the steam bath for 6hours. It is then cooled, filtered and concentrated, to give3-benzoyloxy-4-methoxybenzoyl chloride (28.7 g), m.p. 120-122° C.

REFERENCE EXAMPLE 11

By proceeding in a manner similar to that described in Example 8, butusing 3-benzoyloxy-4-methoxybenzoyl chloride (that is prepared asdescribed in Reference Example 10) and 4-amino-3,5-dichloropyridine(that is prepared as described in Reference Example 4) as startingmaterials, there is preparedN-(3,5-dichloropyrid-4-yl)-3-benzoyloxy-4-methoxybenzamide, m.p.191-192° C.

REFERENCE EXAMPLE 12

A solution of N-(3,5-dichloropyrid-4-yl)-3-benzoyloxy-4-methoxybenzamide(13.4 g; that is prepared as described in Reference Example 11) inmethanol (160 mL) and water (60 mL) is treated with anhydrous potassiumcarbonate (18 g), and stirred overnight at room temperature. It is thenbrought to pH 7 by treatment with dilute hydrochloric acid (2 N), andconcentrated. The residue is treated with water (100 mL) and filtered,and the resulting solid is dried, to giveN-(3,5-dichloropyrid-4-yl)-3-hydroxy-4-methoxybenzamide (8.8 g), m.p.227-228° C.

REFERENCE EXAMPLE 13

By proceeding in a manner similar to that described in Reference Example2, but using the appropriate quantities of3-(exo-8,9,10-trinorbornyl-2-oxy)-4-methoxybenzaldehyde (that isprepared as described in Reference Example 7) and(R)-3-(exo-8,9,10-trinorbornyl-2-oxy)-4-methoxybenzaldehyde and(S)-3-(exo-8,9,10-trinorbornyl-2-oxy)-4-methoxybenzaldehyde [that aresimilarly prepared from (R)-endo-8,9,10-trinorborneol and(S)-endo-8,9,10-trinorborneol or as described in the specification ofEuropean Patent Publication No. 0428302A2] there are prepared:

3-(exo)-8,9,10-trinorbornyl-2-oxy-4-methoxybenzoic acid, m.p. 155-156°C.;

(R)-3-(exo)-8,9,10-trinorbornyl-2-oxy-4-methoxybenzoic acid, m.p.155-156° C.; and

(S)-3-(exo)-8,9,10-trinorbornyl-2-oxy-4-methoxybenzoic acid, m.p.155-156° C.

REFERENCE EXAMPLE 14

By proceeding in a manner similar to that described in Reference Example3, but using the appropriate quantities of the corresponding benzoicacid derivatives (that are prepared as described hereinbefore inReference Example 13) there are prepared:

3-(exo)-8,9,10-trinorbornyl-2-oxy-4-methoxybenzoyl chloride;

(R)-3-(exo)-8,9,10-trinorbornyl-2-oxy-4-methoxybenzoyl chloride; and

(S)-3-(exo)-8,9,10-trinorbornyl-2-oxy-4-methoxybenzoyl chloride; each inthe form of oils.

REFERENCE EXAMPLE 15

A solution of methyl 4-chloro-3-nitrobenzoate (28 g) in acetone (250 mL)is treated portionwise with sodium thiomethoxide (10 g) and the mixtureis stirred overnight at room temperature. After filtration, the solutionis concentrated and water (300 mL) is added to the residue. The yellowsolid is filtered off and subjected to flash chromatography eluting witha mixture of diethyl ether and pentane (1:4 v/v), to give methyl4-methylthio-3-nitrobenzoate (18.5 g), in the form of a yellow solid,m.p. 118-120° C.

REFERENCE EXAMPLE 16

A stirred solution of methyl 4-methylthio-3-nitrobenzoate (6.82 g) inmethanol (350 mL) is hydrogenated using a 5% w/w palladium on charcoalcatalyst (0.8 g) at room temperature for 48 hours. After filtration thesolution is concentrated, to give methyl 3-amino-4-(methylthio)benzoate(3.5 g), in the form of a pale yellow solid m.p. 63-65° C.

REFERENCE EXAMPLE 17

A stirred solution of concentrated hydrochloric acid (3.2 mL) in water(3.6 mL) at from 0° C. to 5° C. is treated with methyl3-amino-4-(methylthio)benzoate (1.97 g), followed by a solution ofsodium nitrite (0.82 g) in water (2 mL), at such a rate that thetemperature remained from 0° C. to 5° C. The mixture is then allowed towarm to room temperature and it is stirred for a further period of 1hour. The reaction mixture is treated with water (30 mL) and then heatedto 55-60° C., until the evolution of nitrogen ceased (4 hours). Themixture is extracted with dichloromethane (2×100 mL) and the combinedorganic extracts are dried and concentrated. The resulting brown oil issubjected to flash chromatography, eluting with a mixture of diethylether and pentane (1:4 v/v), to give methyl3-hydroxy-4-(methylthio)benzoate (0.6 g) in the form of a yellow solid.

REFERENCE EXAMPLE 18

A stirred solution of methyl 3-hydroxy-4(methylthio)benzoate (1.98 g) indry dimethylformamide (40 mL) is treated with sodium hydride (0.44 g;60% dispersion in mineral oil; 11 mmol) and the solution is stirred fora further 25 minutes. The reaction mixture is treated with cyclopentylbromide (1.64 g), stirred at 60° C. for 3 hours, and then concentrated.The resulting residue is partitioned between dichloromethane (50 mL) andwater (50 mL), the aqueous layer is extracted with dichloromethane (50mL), and the combined organic layers are dried and concentrated, to givea red oil. The oil is subjected to flash chromatography, eluting with amixture of diethyl ether and pentane (1:9 v/v), to give methyl3-cyclopentyloxy-4-(methylthio)benzoate (1.9 g), m.p. 53-55° C.

REFERENCE EXAMPLE 19

A suspension of methyl 3-cyclopentyloxy-4-(methylthio)benzoate (0.8 g)in methanol (10 mL) and water (5 mL) is treated with potassium carbonate(0.48 g) and the mixture is heated at reflux for 7 hours. The mixture isconcentrated, and the resulting residue is partitioned between diethylether (20 mL) and water (20 mL). The aqueous layer is separated,acidified to pH 1 by treatment with dilute hydrochloric acid (2 N), andextracted with dichloromethane (2×25 mL). The combined organic extractsare dried and concentrated, to give3-cyclopentyloxy-4-(methylthio)benzoic acid (0.7 g) in the form of awhite solid m.p. 150-152° C.

REFERENCE EXAMPLE 20

3-Cyclopentyloxy-4-(methylthio)benzoic acid (0.7 g) is dissolved i ntoluene (20 mL) and heated at 80° C. for 1 hour 30 minutes in thepresence of thionyl chloride (5 mL). The reaction mixture isconcentrated to give 3-cyclopentyloxy-4-(methylthio)benzoyl chloride(0.76 g), in the form of a yellow oil.

REFERENCE EXAMPLE 21

A cold (0° C.) solution of diisopropyl azodicarboxylate (5.1 g) in drytetrahydrofuran (10 mL) is treated with a solution of triphenylphosphine(6.6 g) in dry tetrahydrofuran (10 mL). The resulting creamy precipitateis stirred in the cold for a further 0.5 hours, and treated with asolution of endo-8,9,10-trinorborneol (1.4 g) in dry tetrahydrofuran (10mL), followed by a solution of methyl 3-hydroxy-4-(methylthio)benzoate(5.0 g) in dry tetrahydrofuran (10 mL) (that is prepared as described inReference Example 17). The resulting mixture is then heated at refluxfor 17 hours, cooled, poured into water (300 mL) and extracted withdiethylether (2×250 mL). The combined ethereal extracts are dried oversodium sulfate and evaporated under reduced pressure to give an oil,which is subjected to flash chromatography on silica gel withdichloromethane/pentane (gradient elution 1:4 v/v to 3:1 v/v) to givemethyl 3-(exo)-8,9,10-trinorbornyl-2-oxy-4-(methylthio)benzoate (3.0 g)as a colorless oil.

By proceeding in a similar manner, but replacingendo-8,9,10-trinorborneol used as starting material by the appropriatequantities of (R)-endo-8,9,10-trinorborneol and(S)-endo-8,9,10-trinorborneol [that are prepared as described inEuropean Patent Publication No. 0 428 302 A2] there are prepared:

(R) methyl 3-(exo)-8,9,10-trinorbornyl-2-oxy-4-(methylthio)benzoate,m.p. 63-64° C. (from heptane), [a]_(D) ²² -12.9° (c=0.72, CH₂ Cl₂); and

(S) methyl 3-(exo)-8,9,10-trinorbornyl-2-oxy-4-(methylthio)benzoate,m.p. 65-66° C. (from heptane), [a]_(D) ²² +31.5° (c=1.20, CH₂ Cl₂).

REFERENCE EXAMPLE 22

By proceeding in a manner similar to that described in Reference Example19, but using the appropriate quantities of methyl 3-(exo)-8,9,10,trinorbornyl-2-oxy-4-(methylthio)benzoate, (R) methyl3-(exo)-8,9,10-trinorbornyl-2-oxy-4-(methylthio)benzoate and (S) methyl3-(exo)-8,9,10-trinorbornyl-2-oxy-4-(methylthio)benzoate (that areprepared as described in Reference Example 21) there are prepared:

3-(exo)-8,9,10-trinorbornyl-2-oxy-4-(methylthio)benzoic acid;

(R)-(exo)-8,9,10-trinorbornyl-2-oxy-4-(methylthio)benzoic acid, m.p.151-152° C. (from heptane/toluene), [a]_(D) ²² +10.9° (c=0.92, CH₂ Cl₂);and

(S)-(exo)-8,9,10-trinorbornyl-2-oxy-4-(methylthio)benzoic acid, m.p.167-168° C. (from heptane/toluene), [a]_(D) ²⁰ +23.8° (c=1.48, CH₂ Cl₂).

REFERENCE EXAMPLE 23

To 3-(exo)-8,9,10-trinorbornyl-2-oxy-4-(methylthio)benzoic acid (2.7 g),that is prepared as in Reference Example 22) in dry dichloromethane (30mL) is added oxalyl chloride (1.3 mL). The resulting mixture is stirredat room temperature for 2 hours and then concentrated to give3-(exo)-8,9,10-trinorbornyl-2-oxy-4-(methylthio)benzoyl chloride as anoff yellow oil (2.8 g).

By proceeding in a similar manner but replacing3-(exo)-8,9,10-trinorbornyl-2-oxy-4-(methyltbio)benzoic acid used asstarting material by the appropriate quantities of (R)3-(exo)-8,9,10-trinorbornyl-2-oxy-4-(methylthio)benzoic acid and (S)3-(exo)-8,9,10-trinorbornyl-2-oxy-4-(methylthio)benzoic acid (that areprepared as described in Reference Example 22) there are prepared:

(R)-3-(exo)-8,9,10-trinorbornyl-2-oxy-4-(methylthio)benzoyl chloride;and

(S)-3-(exo)-8,9,10-trinorbornyl-2-oxy-4-(methylthio)benzoyl chloride.

REFERENCE EXAMPLE 24

Concentrated sulfuric acid (27 6 g) is slowly added to a stirredsuspension of 3-hydroxy-4-nitrobenzoic acid (54.9 g, 0.3 mol) inmethanol (135 mL) at ambient temperature. The resulting yellow slurry isstirred at reflux giving a complete solution after 30 minutes and thestirring at reflux is continued for 3 hours. The mixture is allowed tocool then diluted with water (600 mL) and the resulting mixture is thenextracted with toluene (2×250 mL). The combined organic extract iswashed with saturated aqueous sodium hydrogen carbonate solution (1×300mL) and then dried (MgSO₄). The solvent is then removed under reducedpressure to give a yellow solid residue (54.9 g. 92.8%) which isidentified as methyl 3-hydroxy-4-nitrobenzoate m.p. 92-94° C. [Elementalanalysis: C,49.1; H,3.57; N,7.3%; calculated: C,48.74; H,3.58; N,7.1%].

REFERENCE EXAMPLE 25

Cyclopentyl bromide (20 g, 134 mmol) is added slowly (over 30 minutes)to a stirred suspension of potassium carbonate (27.6 g, 200 mmol) inN,N'-dimethylimidazolidinone (75 mL) containing 3-hydroxy-4-nitrobenzoicacid (9.15 g, 50 mmol) at 85° C. and then stirring is continued for 14hours. The mixture is allowed to cool and then filtered. The filtrate isdiluted with water (100 mL) then extracted with toluene (2×100 mL). Thecombined organic extract is dried over magnesium sulfate and then thesolvent is removed under reduced pressure to give a brown mobile oil.This oil is subjected by flash chromatography on silica gel(dichloromethane as eluent) and the eluent evaporated under reducedpressure to give cyclopentyl 3-cyclopentyloxy-4-nitrobenzoate (10.2 g,81.6%) as a yellow solid m.p. 45.5-46.5° C. [Elemental analysis: C,63.7;H,6.66; N,4.37%; calculated: C,63.93; H,6.63; N, 4.39%].

REFERENCE EXAMPLE 26

Cyclopentyl bromide (38.7 g, 0.26 mol) is added slowly (over 1 hour) toa stirred suspension of potassium carbonate (41.4 g, 0.3 mol) inN,N-dimethylformamide (200 mL) containing methyl3-hydroxy-4-nitrobenzoate (39.4 g, 0.2 mol) at 65° C. and then thestirring is continued for 4 hours. The mixture is allowed to cool andthen filtered. The filtrate is diluted with water (700 mL) containingsodium chloride (50 g) and then extracted with toluene (3×200 mL). Thecombined organic extract is washed with 1N sodium hydroxide solution(1×200 mL) and then water (2×200 mL) and then evaporated under reducedpressure to give methyl 3-cyclopentyloxy-4-nitrobenzoate (54.2 g, 100%)as a pale green solid which is used without further purification.

REFERENCE EXAMPLE 27

Sodium thiomethoxide (8.05 g, 0.115 mol) is added portionwise to astirred solution of methyl 3-cyclopentyloxy-4-nitrobenzoate (26.5 g, 0.1mol) in N,N'-dimethylimidazolidinone (200 mL) at ambient temperatureunder an atmosphere of nitrogen and stirring continued for 4 hours. Themixture is then diluted with water (1200 mL) containing sodium chloride(200 g) and extracted with ethyl acetate (2×300 mL). The combinedextract is washed with saturated brine (2×300 mL) and then evaporatedunder reduced pressure to give methyl3-cyclopentyloxy-4-(methylthio)benzoate (24.4 g, 91.7%) as an orangebrown solid which is used without further purification.

REFERENCE EXAMPLE 28

Sodium thiomethoxide (0.177 g, 2.5 mmol) is added portionwise to astirred solution of cyclopentyl 3-cyclopentyloxy-4-nitrobenzoate (0.64g, 2 mmol) in N,N'-dimethylimidazolidinone (10 mL) at ambienttemperature under an atmosphere of nitrogen and stirring continued for 4hours. The mixture is then diluted with water (100 mL) containing sodiumchloride (15 g) and extracted with ethyl acetate (2×50 mL). The combinedextract is washed with saturated brine (1×100 mL) and then dried overmagnesium sulfate and evaporated under reduced pressure to givecyclopentyl 3-cyclopentyloxy-4-(methylthio)benzoate (0.52 g, 81%) as abrown viscous oil which is used without further purification.

REFERENCE EXAMPLE 29

Method 1

A solution of methyl 3-cyclopentyloxy-4-(methylthio)benzoate (24.3 g,91.4 mmol) in water (200 mL) and ethanol (50 mL) containing sodiumhydroxide (18.3 g, 460 mmol) is heated under reflux for 3 hours. Thesolution is then poured into water (750 mL) and 1 N acetic acid is addeddropwise with stirring to between pH 5-6. The solid which separates iscollected by filtration, washed with water (4×100 mL) and dried giving3-cyclopentyloxy-4-(methylthio)benzoic acid (21.1 g, 91.7%) as a creamsolid m.p. 158-160° C. [Elemental analysis: C,61.5; H,6.31%; calculated:C,61.88; H,6 39%].

Method 2

A solution of cyclopentyl 3-cyclopentyloxy-4-(methylthio)benzoate (0.5g, 1.5 mmol) in water (30 mL) and methanol (10 mL) containing sodiumhydroxide (1 g, 25 mmol) is heated under reflux for 3 hours. Thesolution is then poured into water (60 mL) and acetic acid is addeddropwise with stirring to between pH 5-6. The solid which separates iscollected by filtration, washed with water (5×10 mL) and dried giving3-cyclopentyloxy-4-(methylthio)benzoic acid (0.35 g, 88.6%) as a creamsolid m.p. 158-160° C.

REFERENCE EXAMPLE 30

A solution of 3-hydroxy-4-methoxybenzaldehyde (14.20 g) in drydimethylformamide (300 mL) is treated portionwise with sodium hydride(60% dispersion in oil; 3.70 g) at room temperature under nitrogen.3-Chlorocyclo-pentene (9.6 mL) is added and the resulting mixture isstirred overnight. The solvent is then removed under reduced pressureand the residue is partitioned between water (500 mL) anddichloromethane (500 mL) and the aqueous layer is further extracted withdichloromethane (500 mL). The combined organic extracts are dried andevaporated under reduced pressure and the residue is subjected to flashchromatography on silica gel, eluting with a mixture of ethyl acetateand pentane (1:1 v/v), to give3-cyclopent-2-enyloxy-4-methoxybenzaldehyde, in the form of a pale brownoil (11.2 g).

REFERENCE EXAMPLE 31

A solution of 3-cyclopent-2-enyloxy-4-methoxybenzaldehyde (7.70 g) int-butanol (160 mL) and 2-methyl-2-butene (40 mL) is treated dropwisewith an aqueous solution (150 mL) containing sodium chlorite (80%technical grade; 4.39 g) and sodium dihydrogen phosphate (38.49 g), andleft to stand overnight. The resulting mixture is extracted withdichloromethane (2×250 mL), and the combined organic layers are driedover sodium sulfate, the solvent is removed under reduced pressure, andthe resulting residue is recrystallized from ethyl acetate, to give3-cyclopent-2-enyloxy-4-methoxybenzoic acid (5.89 g), in the form of acolorless solid. m.p. 160-163° C. [Elemental analysis: C,66.4; H,6.0%;calculated: C,66.7; H,6.0%].

REFERENCE EXAMPLE 32

A solution of 3-cyclopent-2-enyloxy-4-methoxybenzoic acid (5.89 g) indry dichloromethane (50 mL) under nitrogen at room temperature istreated with triethylamine (10.50 mL), followed by oxalyl chloride (2.40mL). The resulting mixture is stirred for 2.5 hours, then most of thesolvent is removed under reduced pressure, and the resulting residue istaken up in dry tetrahydrofuran (50 mL) and filtered through a pad ofdiatomaceous earth. The resulting solution, containing3-cyclopent-2-enyloxy-4-methoxybenzoyl chloride is used immediatelywithout further purification.

REFERENCE EXAMPLE 33

A stirred suspension of sodium hydride (60% in oil, 0.88 g) in drydimethylformamide (44 mL) under nitrogen at between 5-10° C. is treatedwith a solution of 3-hydroxy-4-methoxy benzaldehyde (3.35 g) in drydimethylformamide (6.3 mL). The resulting mixture is allowed to warm toroom temperature and stirred for 40 minutes before recooling to between5-10° C. A solution of 4-(p-toluenesulfonoxy)cyclopentene (5.24 g) indry dimethylformamide (12.6 mL) is added dropwise maintaining thetemperature below 10° C. The resulting mixture is allowed to warm toroom temperature, left to stand for 46 hours, and then poured into 5%aqueous potassium carbonate (305 mL). t-Butyl methyl ether is added (150mL), and the layers are thoroughly stirred and separated. The aqueouslayer is further extracted with t-butyl methyl ether (2×75 mL), thecombined organic extracts are washed with water (3×30 mL) and dried overmagnesium sulfate. The solvent is removed under reduced pressure and theresulting residue is subjected to flash chromatography on silica gel,eluting with mixtures of ethyl acetate and pentane (1:10 to 3:10), togive 3-cyclopent-3-enyloxy-4-methoxybenzaldehyde as a pale amber viscousoil that slowly crystallizes on standing (1.75 g). Recrystallization ofa portion (0.5 g) from cyclohexane gives an analytically pure sample(0.4 g), m.p. 60-62° C. [Elemental analysis: C,71.8; H,6.5%; calculated:C,71.5; H,6.8%].

REFERENCE EXAMPLE 34

A stirred solution of 3-cyclopent-3-enyloxy-4-methoxybenzaldehyde (1.75g) in t-butanol (36.5 mL) and 2-methyl-2-butene (9.0 mL) is treateddropwise with an aqueous solution (34 mL) containing sodium chlorite(80% technical grade; 1.0 g) and sodium dihydrogen phosphate (8.75 g).The resulting mixture is further stirred for 5 hours, the layers areseparated and the aqueous layer is extracted with t-butyl methyl ether(3×30 mL). The combined organic layers are washed with water (2×15 mL),dried over sodium sulfate and the solvent removed under reducedpressure. The resulting residue is recrystallized from ethyl acetate togive 3-cyclopent-3-enyloxy-4-methoxybenzoic acid (1.31 g), in the formof a colorless solid, m.p. 171-173° C. [Elemental analysis: C,66.6;H,6.0%; calculated: C,66.7; H,6.0%].

REFERENCE EXAMPLE 35

A solution of 3-cyclopent-3-enyloxy-4-methoxybenzoic acid (1.33 g) indry tetrahydrofuran (20 mL) under nitrogen at room temperature istreated with triethylamine (2.36 mL), followed by oxalyl chloride (0.70mL). The resulting mixture is stirred for 1 hour and then filteredthrough a pad of diatomaceous earth. The solid collected is washed withdry tetrahydrofuran (10 mL). The resulting combined filtrates,containing 3-cyclopent-3-enyloxy-4-methoxybenzoyl chloride, is usedimmediately without further purification.

REFERENCE EXAMPLE 36

A stirred solution of sodium hydroxide (16.8 g) in water (32 mL) at 20°C. is treated with dimethyl sulfoxide (560 mL). It is then treated with3,4-dihydroxy-benzaldehyde (56.9 g), portionwise during 5 minutes, whilekeeping the temperature at 20° C. It is then treated with benzyl bromide(49.7 mL), portionwise, at 20° C. The solution is then heated at 80° C.for 6 hours and then allowed to stand at room temperature overnight.After dilution with ice-water (2240 mL) the solution is extracted withdiethyl ether (1×1000 mL, 2×250 mL). The combined ether extracts arewashed with water, dried over magnesium sulfate and concentrated, togive an oily solid, which is recrystallized from a mixture of ethylacetate and isopropanol, to give 4-benzyloxy-3-hydroxybenzaldehyde (60.9g), in the form of pale yellow crystals, m.p. 118-120° C.

REFERENCE EXAMPLE 37

A stirred solution of 4-benzyloxy-3-hydroxybenzaldehyde (60.9 g; that isprepared as described in Reference Example 36) in dry dimethylformamide(270 mL) under nitrogen is treated portionwise with potassium carbonate(79.5 g). After stirring at room temperature for 45 minutes, it istreated with cyclopentyl bromide (34.3 mL), and the resulting suspensionis heated at 60° C. for 8 hours. After cooling, the solution isevaporated to low bulk under reduced pressure, to give an oil. This oilis treated with water (250 mL) and diethyl ether (300 mL), and theaqueous layer is washed with further quantities of diethyl ether (2×50mL). The combined ethereal extracts are washed with brine (1×50 mL) andwith water (3×50 mL), dried over magnesium sulfate and evaporated. Theresulting residue is crystallized from methanol, to give4-benzyloxy-3-cyclopentyloxybenzaldehyde (79 g), m.p. 55-56° C.[Elemental analysis: C,77.1; H,6.9%; calculated: C,77.0; H,6.8%].

REFERENCE EXAMPLE 38

A rapidly stirred solution of 4-benzyloxy-3-cyclopentyloxybenzaldehyde(10.5 g; that is prepared as described in Reference Example 37) inglacial acetic acid (100 mL) is treated with sulfamic acid (4.85 g) andstirred at room temperature for 10 minutes. The solution is then cooledin an ice bath and treated with a solution of sodium chlorite (4.2 g) inwater (100 mL) during 15 minutes at 13-15° C. During the addition awhite precipitate forms and, because stirring becomes difficult, afurther quantity of glacial acetic acid (60 mL) is added. After warningto room temperature, the solution is stirred for a further 6 hours andfurther quantities of sodium chlorite (1.6 g) and sulfamic acid (1.7 g)are added. The mixture is poured onto water and the resulting solid isfiltered off and dried, to give 3-cyclopentyloxy-4-benzyloxybenzoic acid(10 g).

REFERENCE EXAMPLE 39

A solution of 3-cyclopentyloxy-4-benzyloxybenzoic acid (5.1 g; that isprepared as described in Reference Example 38) in methanol (150 mL) andconcentrated sulfuric acid (1 mL) is heated at reflux for 6 hours, andthen it is cooled and concentrated in vacuo. The resulting residue istreated with ethyl acetate (150 mL) and saturated aqueous sodiumbicarbonate solution (50 mL). The organic layer is collected, dried andevaporated. The resulting oil is subjected to flash chromatography onsilica gel, using a mixture of ethyl acetate and pentane (1:4 v/v) aseluent to give methyl 3-cyclopentyloxy-4-benzyloxybenzoate (4.8 g), inthe form of a white solid, m.p. 58-59° C.

REFERENCE EXAMPLE 40

A solution of methyl 3-cyclopentyloxy-4-benzyloxybenzoate (2.64 g; thatis prepared as described in Reference Example 39) in methanol (120 mL)is treated with palladium on charcoal (5%,0.5 g) and ammonium formate(2.0 g) and heated at reflux for 45 minutes. The catalyst is filteredoff through a pad of diatomaceous earth and washed with methanol. Thefiltrate and washings are evaporated under reduced pressure, and theresulting residue is subjected to flash chromatography on silica gelusing a mixture of diethyl ether an pentane 1:1 v/v), to give methyl3-cyclopentyloxy-4-hydroxybenzoate (1.8 g), in the form of a creamsolid, m.p. 73-75° C.

REFERENCE EXAMPLE 41

A solution of methyl 3-cyclopentyloxy-4-hydroxybenzoate (0.7 g; that isprepared as described in Reference Example 40) in dimethylformamide (15mL) is treated with potassium carbonate (0.28 g) and potassium iodide(0.2 g). Chlorodifluoromethane is then bubbled through the reactionmixture at a very slow rate and the reaction mixture is heated at 70-75°C. for 5 hours. The mixture is then treated with water (50 mL) andextracted with ethyl acetate (2×50 mL). The combined ethyl acetateextracts are dried over magnesium sulfate, evaporated under reducedpressure, and subjected to flash chromatography on silica gel using amixture of diethyl ether and pentane (1 :1 v/v), to give methyl3-cyclopentyloxy-4-difluoromethoxybenzoate, in the form of a pale yellowoil (0.65 g).

REFERENCE EXAMPLE 42

A solution of methyl 3-cyclopentyloxy-4-difluoromethoxybenzoate (0.6 g;that is prepared as described in Reference Example 41) in methanol (10mL) is treated with potassium carbonate (0.35 g) and water (4 mL), andthen it is heated at reflux for 3 hours. Methanol is evaporated offunder reduced pressure, and the residue is dissolved in water (40 mL).The solution is washed with diethyl ether (40 mL), acidified withconcentrated hydrochloric acid, and extracted with ethyl acetate (3×40mL). The combined ethyl acetate extracts are dried over magnesiumsulfate and evaporated under reduced pressure, to give3-cyclopentyloxy-4-difluoromethoxybenzoic acid (0.47 g), in the form ofa white solid, m.p. 126-128° C.

REFERENCE EXAMPLE 43

A mixture of 3-cyclopentyloxy-4-difluoromethoxybenzoic acid (0.47 g;that is prepared as described in Reference Example 42) and thionylchloride (4 mL) in toluene (10 mL) is heated at 80° C. for 2 hours, andthen evaporated under reduced pressure, to give3-cyclopentyloxy4-difluoromethoxybenzoyl chloride (0.48 g), in the formof a pale yellow low melting solid, which is used without furtherpurification.

REFERENCE EXAMPLE 44

A stirred solution of chlorosulfonic acid (90 mL) at room temperature istreated with p-anisic acid (40 g), portionwise, during 30 minutes. Whenthe addition is complete, the mixture is stirred at 90° C. for 75minutes, then it is cooled and poured onto ice. The white precipitate iscollected and dissolved in ethyl acetate (300 mL). The organic extractis washed with brine (2×250 mL), dried over magnesium sulfate, andconcentrated, to give 3-chlorosulfonyl-4-methoxybenzoic acid (34 g), inthe form of a white solid m.p. 168-170° C.

REFERENCE EXAMPLE 45

A stirred solution of 3-chlorosulfonyl-4-methoxybenzoic acid (58 g; thatis prepared as described in Reference Example 44) in glacial acetic acid(250 mL) at 40° C. is treated during 15 minutes with a solution ofstannous chloride (107 g) in concentrated hydrochloric acid. The mixtureis heated at reflux for 2 hours and the hot mixture is then poured intowater (2 L) with vigorous stirring. The resulting solid is filtered offand dried, to give crude 3-mercapto-4-methoxybenzoic acid (34 g).

REFERENCE EXAMPLE 46

A solution of 3-mercapto-4-methoxybenzoic acid (that is prepared asdescribed in Reference Example 45 from 58 g of3-chlorosulfonyl-4-methoxybenzoic acid) in dimethylformamide (400 mL) istreated with potassium carbonate (120 g) and cyclopentyl bromide (60 g).The solution is heated at 50° C. for 3 hours, and then it is cooled andpoured into water (3 L) containing concentrated hydrochloric acid (250mL). The resulting solid is filtered off and dried, to give3-cyclopentylthio-4-methoxybenzoic acid (10.5 g), in the form of a whitecrude solid.

REFERENCE EXAMPLE 47

A solution of 3-cyclopentylthio-4-methoxybenzoic acid (9 g; that isprepared as described in Reference Example 46) in dry dichloromethane(90 mL) under nitrogen is treated with oxalyl chloride (6.2 mL). Afterstirring at room temperature for 2 hours, the mixture is evaporated anddried under high vacuum, to give 3-cyclopentylthio-4-methoxybenzoylchloride.

REFERENCE EXAMPLE 48

A mixture of 3-chlorosulfonyl-4-methoxybenzoic acid (4.76 g; that isprepared as described in Reference Example 44) in dry toluene (500 mL)stirred at room temperature is treated with triphenylphosphine (19.9 g)in one portion. The mixture is stirred and heated at 80° C. overnight,and then it is cooled, and treated with water (25 mL) and dioxane (25mL), and the resulting solution is heated on a steam bath for 1 hour.The reaction mixture is allowed to cool to room temperature, and theorganic layer is collected and concentrated. The resulting residue ispartitioned between ethyl acetate (200 mL) and aqueous sodium hydroxidesolution (500 mL; 2 N). The aqueous layer is separated, acidified bytreatment with concentrated hydrochloric acid, and extracted with ethylacetate (100 mL). The extract is washed with water (100 mL), dried overmagnesium sulfate and concentrated, to give 3-mercapto-4-methoxybenzoicacid in the form of a white solid (3.4 g), m.p. 208-210° C.

REFERENCE EXAMPLE 49

A stirred solution of 3-mercapto-4-methoxybenzoic acid (3.34 g; that isprepared as described in Reference Example 48) in tetrahydrofuran (80mL) at room temperature under nitrogen is treated portionwise withsodium hydride (60% dispersion in oil; 1.58 g; 40 mmol). The mixture iscautiously warmed to 50° C., and vigorous effervescence ensues. Afterhydrogen evolution has ceased, the mixture is treated dropwise with2-bromopropane (2.2 g) and the solution is stirred at 50° C. for 2hours. Dimethylformamide (40 mL) is added and the reaction mixture isstirred for a further 1 hour at 50° C. The solution is concentrated andthe residue is treated with water (100 mL). The resulting solution isacidified by treatment with concentrated hydrochloric acid, andextracted with ethyl acetate (2×100 mL). The combined organic extract iswashed with water (100 mL), dried over magnesium sulfate andconcentrated to give, after trituration with pentane,3-isopropylthio-4-methoxybenzoic acid (2.6 g), in the form of a palecream solid, m.p. 159-161° C. [Elemental analysis: C,58.4; H,6.25%;calculated: C,58.38; H,6.2%].

REFERENCE EXAMPLE 50

A solution of 3-isopropylthio-4-methoxybenzoic acid (2.5 g; that isprepared as described in Reference Example 49) in toluene (25 mL) anddimethylformamide (0.2 mL) is treated with thionyl chloride (2.5 mL) andthe solution is stirred at 60° C. for 3 hours. The solution isconcentrated, treated with toluene (10 mL) and again evaporated todryness, to give 3-isopropylthio-4-methoxybenzoyl chloride (2.7 g), inthe form of a light brown oil.

REFERENCE EXAMPLE 51

A solution of methyl 4-chloro-3-nitrobenzoate (28 g) in acetone (250 mL)is treated portionwise with sodium thiomethoxide (10 g) and the mixtureis stirred overnight at room temperature. After filtration, the solutionis concentrated and water (300 mL) is added to the residue. The yellowsolid is filtered off and subjected to flash chromatography eluting witha mixture of diethyl ether and pentane (1:4 v/v), to give methyl4-methylthio-3-nitrobenzoate (18.5 g), in the form of a yellow solid,m.p. 118-120° C.

REFERENCE EXAMPLE 52

A stirred solution of methyl 4-methylthio-3-nitrobenzoate (6.82 g; thatis prepared as described in Reference Example 51) in methanol (350 mL)is hydrogenated using a 5% w/w palladium on charcoal catalyst (0.8 g) atroom temperature for 48 hours. After filtration the solution isconcentrated, to give methyl 3-amino-4-(methylthio)benzoate (3.5 g), inthe form of a pale yellow solid, m.p. 63-65° C.

REFERENCE EXAMPLE 53

A stirred solution of concentrated hydrochloric acid (3.2 mL) in water(3.6 mL) at from 0° C. to 5° C. is treated with methyl3-amino-4-(methylthio)benzoate (1.97 g; that is prepared as described inReference Example 52), followed by a solution of sodium nitrite (0.82 g)in water (2 mL), at such a rate that the temperature remains from 0° C.to 5° C. The mixture is then allowed to warm to room temperature and itis stirred for a further period of 1 hour. The reaction mixture istreated with water (30 mL) and then heated to 55-60° C., until theevolution of nitrogen ceased (4 hours). The mixture is extracted withdichloromethane (2×100 mL) and the combined organic extracts are driedand concentrated. The resulting brown oil is subjected to flashchroma-tography, eluting with a mixture of diethyl ether and pentane(1:4 v/v), to give methyl 3-hydroxy-4-(methylthio)benzoate (0.6 g) inthe form of a yellow solid.

REFERENCE EXAMPLE 54

A stirred solution of methyl 3-hydroxy-4-(methylthio)benzoate (1.98 g;that is prepared as described in Reference Example 53) in drydimethyl-formamide (40 mL) is treated with sodium hydride (0.44 g of a60% dispersion in mineral oil; 11 mmol) and the solution is stirred fora further 25 minutes. The reaction mixture is treated with cyclopentylbromide (1.64 g), stirred at 60° C. for 3 hours, and then concentrated.The resulting residue is partitioned between dichloromethane (50 mL) andwater (50 mL), the aqueous layer is extracted with dichloromethane (50mL), and the combined organic layers are dried and concentrated, to givea red oil. The oil is subjected to flash chromatography, eluting with amixture of diethyl ether and pentane (1:9 v/v), to give methyl3-cyclopentyloxy-4-(methylthio)benzoate (1.9 g), m.p. 53-55° C.

REFERENCE EXAMPLE 55

A suspension of methyl 3-cyclopentyloxy-4-(methylthio)benzoate (0.8 g;that is prepared as described in Reference Example 54) in methanol (10mL) and water (5 mL) is treated with potassium carbonate (0.48 g) andthe mixture is heated at reflux for 7 hours. The mixture isconcentrated, and the resulting residue is partitioned between diethylether (20 mL) and water (20 mL). The aqueous layer is separated,acidified to pH 1 by treatment with dilute hydrochloric acid (2 N), andextracted with dichloromethane (2×25 mL). The combined organic extractsare dried and concentrated, to give3-cyclopentyloxy-4-(methylthio)benzoic acid (0.7 g) in the form of awhite solid m.p. 150-152° C.

REFERENCE EXAMPLE 56

3-Cyclopentyloxy-4-(methylthio)benzoic acid (0.7 g; that is prepared asdescribed in Reference Example 55) is dissolved in toluene (20 mL) andheated at 80° C. for 1 hour 30 minutes in the presence of thionylchloride (5 mL). Concentration gave3-cyclopentyloxy-4-(methylthio)benzoyl chloride (0.76 g), in the form ofa yellow oil.

REFERENCE EXAMPLE 57

A solution of 4-amino-3,5-dichloropyridine (0.46 g; that is prepared asdescribed in Reference Example 4) in dry dimethylformamide (20 mL) istreated with sodium hydride (0.23 g of a 60% dispersion in mineral oil;2.8 mmol) and the mixture is stirred for 20 minutes. It is then treatedwith a solution of 3-cyclopentyl-oxy-4-(methylthio)benzoyl chloride(0.76 g; that is prepared as described in Reference Example 20) indimethylformamide (10 mL) and stirred at 60° C. for 2 hours. Thesolution is then concentrated and the resulting residue is partitionedbetween water (30 mL) and ethyl acetate (50 mL). The aqueous layer isextracted with ethyl acetate (50 mL) and the combined organic layers aredried, concentrated, and subjected to flash chromatography on silicagel, eluting with a mixture of diethyl ether and pentane (1 :1 v/v), togive N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-(methylthio)benzamide(0.7 g) in the form of a white crystalline solid, m.p. 157-159° C. [NMR(CDCl₃ ]: 8.57 (s,2H), 7.69 (bs,1H), 7.47 (dd,1H,J=8 Hz,J=2 Hz), 7.43(d,1H,J=2 Hz), 7.17 (d,1H,J=8 Hz), 4.95 (m,1H), 2.46 (s,3H),1.98-1.6(m,8H); Elemental analysis: C,54.0; H,4.5; N,7.0; Cl,17.8%;calculated: C,54.4; H,4.6; N,7.05; Cl,17.85%].

REFERENCE EXAMPLE 58

A suspension of 2-methoxyphenylbenzoate (212.5 g) in glacial acetic acid(1 L) is treated dropwise during 1 hour with a solution of bromine (51.5mL) in glacial acetic acid (150 mL). The mixture is stirred for afurther 1 hour, then it is concentrated and the residue is dissolved int-butyl methyl ether (1500 mL). The solution is washed with water (500mL) and with saturated aqueous sodium bicarbonate solution. The solutionis then dried, filtered and concentrated, to give2-benzoyloxy-4-bromoanisole (205.8 g), in the form of a white solid,m.p. 73-75° C.

REFERENCE EXAMPLE 59

A solution of 2-benzoyloxy-4-bromoanisole (5 g) and sodium hydroxide (3g) in water (5 mL) and ethanol (50 mL) is heated at reflux for 1 hour 30minutes. It is then evaporated and the residue is triturated with water(20 mL) and concentrated hydrochloric acid (10 mL) and extracted withdichloromethane (150 mL). The organic solution is washed with saturatedaqueous sodium bicarbonate solution (3×25 mL), dried, and concentrated,to give 5-bromo-2-methoxyphenol (3.25 g), in the form of a whitecrystalline solid, m.p. 67-68° C.

REFERENCE EXAMPLE 60

A stirred solution of 5-bromo-2-methoxyphenol (74 g) and anhydrouspotassium carbonate (73.6 g) in dry dimethylformamide (500 mL) istreated with cyclopentyl bromide (80.5 g) and the solution is heated at60° C. for 16 hours. It is then concentrated, and the resulting residueis triturated with water (250 mL), and extracted with dichloromethane(3×250 mL). The combined extracts are dried and evaporated, to give3-cyclopentyloxy-4-methoxyphenyl bromide (95.5 g), in the form of alight brown oil.

REFERENCE EXAMPLE 61

A solution of butyl lithium in hexane (5.1 mL; 2.5 M) is treated with asolution of 3-cyclopentyloxy-4-methoxyphenyl bromide (3.45 g) in drytetrahydrofuran (30 mL) at -70° C. and the solution is then stirred at-70° C. for 1 hour. It is then treated dropwise with2,6-dichlorophenylacetaldehyde (2.4 g), while keeping the temperaturebelow -60° C. When the addition is complete the temperature is allowedto rise to room temperature and the solution is stirred for a further 2hours. The reaction mixture is treated with aqueous ammonium chloridesolution (50 mL) and the solution is extracted with diethyl ether (2×200mL). The combined extracts are dried and concentrated, to give a yellowoil, which is subjected to flash chromatography, eluting with a mixtureof diethyl ether and pentane (1:8 v/v), to give1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(2,6-dichlorophenyl)ethanol (1.6g), in the form of a white solid, m.p. 87-89° C.

REFERENCE EXAMPLE 62

A solution of diisopropylamine (10.5 mL) in dry tetrahydrofuran (150 mL)is cooled to -75° C. and treated with a solution of butyl lithium inhexane (30 mL; 2.5 M) during 10 minutes. After stirring for 1 hour at-75° C. the mixture is treated with a solution of 3,5-dichloropyridine(10.8 g) in dry tetrahydrofuran (55 mL) and stirred for a further 30minutes. It is then treated with methyl iodide (4.7 mL) in drytetrahydrofuran (10 mL) during 10 minutes, and the solution is allowedto rise gradually to room temperature. After stirring for 2 hours, themixture is treated with saturated aqueous sodium bicarbonate solution(50 mL), followed by diethyl ether (100 mL). The organic layer is washedwith brine, dried and evaporated, and the resulting residue is subjectedto flash chromatography, to give 3,5-dichloro-4-methylpyridine (10.6 g),m.p. 46-47° C.

REFERENCE EXAMPLE 63

A stirred solution of diisopropylamine (9.75 mL) in dry tetrahydrofuran(200 mL) at -70° C. is treated dropwise with a solution of butyl lithiumin hexane (27.2 mL; 2.5 M) and the solution is stirred for 30 minutes.It is then treated with a solution of 3,5-dichloro-4-methylpyridine(10.25 g) in dry tetrahydrofuran (60 mL) during 30 minutes, whilekeeping the temperature below -75° C., and the solution is then stirredfor a further 30 minutes. It is then treated with3-cyclopentyloxy-4-methoxybenzaldehyde (13.92 g) in dry tetrahydrofuran(60 mL) during 15 minutes, and stirred for a further 1 hour 30 minutesat -75° C. The solution is treated with aqueous ammonium chloridesolution and extracted with ethyl acetate (3×100 ml,). The organiclayers are combined, washed with brine, dried and concentrated to lowvolume. The resulting precipitate is filtered off, to give1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(3,5-dichloropyrid-4-yl)ethanol(20.5 g), m.p. 124-125° C.

REFERENCE EXAMPLE 64

Oxalyl chloride (2 mL) is added to a stirred solution of3-cyclopentyloxy-4-methoxybenzoic acid (2.36 g) in dry dichloromethane(50 mL) under a nitrogen atmosphere, and the mixture stirred for 3hours. The reaction mixture is concentrated in vacuo and the residuedissolved in fresh dry dichloromethane (50 mL).N,O-dimethylhydroxylamine hydrochloride (1.12 g) and 2,4,6-collidine(2.9 mL) are added and the mixture stirred for 4 hours. The mixture isdiluted with dichloromethane (100 mL) and washed with saturated aqueoussodium bicarbonate (2×30 mL), 2 M aqueous hydrochloric acid (2×30 mL)and water (20 mL). The dried (MgSO₄) solution is concentrated to anorange oil (3 g) which is purified by flash chromatography (gradientelution ethyl acetate/pentane (2:3 v/v) to ethyl acetate/pentane (2:1v/v) on silica column) to give3-cyclopentyloxy-4,N-dimethoxy-N-methylbenzamide (2.5 g) as a yellowsyrup.

REFERENCE EXAMPLE 65

Hydroxylamine hydrochloride (3.82 g) is added to a solution of3-cyclopentyloxy-4-methoxybenzaldehyde (11.0 g) in acetic anhydride (30mL) and the suspension heated in an oil bath at 100° C. until refluxingstarts. The heating is then removed while the exothermic reactionrefluxes gently. Heating at 100° C. is then continued for a further 1hour. The dark solution is concentrated and the crude product dissolvedin cyclohexane (200 mL). The solution is washed with 5% sodiumbicarbonate solution (2×50 mL), water (2×50 mL) and brine (50 mL), anddried over magnesium sulfate. Upon evaporation, an amber oil (11.8 g)that is purified by flash chromatography (dichloromethane as eluant onsilica column) gives 3-cyclopentyloxy-4-methoxybenzonitrile (8.6 g) as apale yellow oil. [Elemental analysis: C,71.7; H,6.93; N,6.47%;calculated for C₁₃ H₁₅ NO₂ : C,71.87; H,6.96; N,6.45%.].

REFERENCE EXAMPLE 66

A stirred solution of 5-amino-2-methoxyphenol (10 g) in dry dioxane (150mL) is treated portionwise with an oil suspension of sodium hydride(60%; 3 g; 75 mmol) and the mixture is then warmed at 60° C. for 30minutes. It is then treated dropwise with a solution of cyclopentylbromide (9.2 mL) and potassium iodide (50 mg) in dry dimethylformamide(20 mL) and heated at reflux for 5 hours. The mixture is thenconcentrated and the residue is treated with ethyl acetate (200 mL) andwater (200 mL). The organic layer is then separated, washed with water(100 mL), aqueous sodium hydroxide solution (250 mL; 1 N), and withwater (100 mL), and dried over magnesium sulfate. The concentration ofthe reaction mixture gives a dark oil, which is subjected to flashchromatography, eluting with a mixture of n-hexane and ethyl acetate(1:1 v/v), to give 3-cyclopentyloxy-4-methoxyaniline (4.43 g), in theform of an oil.

REFERENCE EXAMPLE 67

A stirred solution of diisopropylamine (14 mL) in dry tetrahydrofuran(150 mL), is treated dropwise with a solution of butyl lithium inhexanes (40 mL; 2.5 M), under nitrogen, while keeping the temperature atbelow -70° C. The resulting mixture is then stirred for a further periodof 30 minutes at below -70° C. The stirred mixture, while it is stillmaintained at below -70° C., is then treated dropwise with a solution of4-picoline (9.3 g) in dry tetrahydrofuran (20 mL). The stirred mixtureis maintained at below -70° C. for a further 45 minutes. The stirredmixture, while it is still maintained at below -70° C., is then treatedwith a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (22.0 g) indry tetrahydrofuran (100 mL), and it is stirred at below -70° C. for afurther 30 minutes. The resulting mixture is then allowed to warm toroom temperature overnight, and then treated with saturated aqueousammonium chloride solution (200 mL). The layers are separated and theaqueous layer is further extracted with ethyl acetate (3×300 mL). Thecombined organic extracts are dried over magnesium sulfate andevaporated to dryness. The resulting residue is recrystallized fromethyl acetate, to give(±)-1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(pyrid-4-yl)ethanol (28.5 g),in the form of a cream solid, m.p. 102-103° C.

REFERENCE EXAMPLE 68

A stirred solution of concentrated hydrochloric acid (1.7 mL) in water(5 mL) from 0° C. and 5° C. is treated with3-cyclopentyloxy-4-methoxyaniline (0.83 g), followed by a solution ofsodium nitrite (0.29 g) in water (0.6 mL), at such a rate that thetemperature remains from 0° C. and 5° C. The resulting solution isstirred for a further 10 minutes, while keeping the temperature below 5°C. The stirred solution, while still maintained at below 5° C., is thentreated dropwise with a solution of sodium tetrafluoroborate (0.88 g) inwater (1.8 mL). The resulting precipitate is filtered off, washed withcold water (3 mL) and dried in vacuo, to give3-cyclopentyloxy-4-methoxyphenyldiazonium tetrafluoroborate (1.24 g) inthe form of a gray solid, m.p. 120° C.

REFERENCE EXAMPLE 69

A stirred solution of 2-methoxyphenyl benzoate (10 g) in dichloromethane(100 mL) from 0-5° C. is treated dropwise with chlorosulfonic acid (2.9mL) and the solution is then stirred for 3 hours from 0-5° C. Theprecipitate which forms is filtered off, washed with colddichloromethane, and dried in vacuo, to give3-benzoyloxy-4-methoxybenzenesulfonic acid (11.45 g), in the form of awhite solid, m.p. 139-140° C.

REFERENCE EXAMPLE 70

A solution of 3-benzoyloxy-4-methoxybenzenesulfonic acid (7.69 g) in drytoluene (70 mL) is treated with thionyl chloride (9 mL), and the mixtureis heated at reflux for 6 hours. Concentration gives3-benzoyloxy-4-methoxybenzenesulfonyl chloride (8.4 g), in the form of abrown oil.

REFERENCE EXAMPLE 71

A stirred solution of 2-chloroaniline (3.3 g) and triethylamine (3.6 mL)in dichloromethane (50 mL) is treated, portionwise, with a solution of3-benzoyloxy-4-methoxybenzenesulfonyl chloride (8.4 g) indichloromethane (50 mL). The reaction mixture is stirred for 6 hours atroom temperature, and then it is washed with water. The organic solutionis dried and concentrated in vacuo, to give an oil, which is subjectedto flash chromatography on silica gel, eluting with diethyl ether, togive a mixture ofN-(3-benzoyloxy-4-methoxyphenylsulfonyl)-2-chloroaniline andN,N-bis(3-benzoyloxy-4-methoxyphenylsulfonyl)-2-chloroaniline.

REFERENCE EXAMPLE 72

A solution of potassium hydroxide (1.27 g) in water (5 mL) and methanol(10 mL) is treated with a mixture ofN-(3-benzoyloxy-4-methoxyphenylsulfonyl)-2-chloroaniline andN,N-bis(3-benzoyloxy-4-methoxyphenylsulfonyl)-2-chloroaniline (2.39 g;that is prepared as described in Reference Example 71) and heated atreflux for 7 hours. After cooling, the solution is neutralized bytreatment with dilute hydrochloric acid (1 N), and the mixture isextracted with dichloromethane (2×75 mL). The combined organic extractsare dried and concentrated, to give a waxy solid. This solid issubjected to flash chromatography on silica gel, eluting with diethylether, to give a mixture ofN-(3-hydroxy-4-methoxyphenylsulfonyl)-2-chloroaniline andN,N-bis(3-hydroxy-4-methoxyphenylsulfonyl)-2-chloroaniline (0.7 g),which is used directly in Example 49.

REFERENCE EXAMPLE 73

Vigorously stirred aqueous ammonia solution (70 mL; 32% w/w) is treateddropwise with warm molten 3-cyclopentyloxy-4-methoxybenzoyl chloride(25.7 g) during a period of 20 minutes, keeping the temperature below20° C. Stirring is continued at 20° C. for 2 hours, and then thesuspension is filtered. The resulting solid is washed with water untilfree of ammonia, and is then dried under vacuum at 40-45° C., to give3-cyclopentyloxy-4-methoxy-benzanide (21.78 g), in the form of a buffsolid.

REFERENCE EXAMPLE 74

A solution of 4-amino-2,3,5-trifluoropyridine [23.1 g; that is preparedas described in J.Med.Chem.30, 340-347,(1987)] and hydrazine hydrate(113 mL) in ethanol (925 mL) is stirred and heated at 100° C. for 2days. The solution is then evaporated to low volume and the resulting4-amino-3,5-difluoro-2-hydrazino-pyridine (22.5 g) is filtered off inthe form of a cream solid.

This damp solid is added portionwise to a stirred solution of cupricsulfate (132 g) in water (462 mL) below 25° C., and the reaction mixtureis stirred at room temperature for 48 hours. The reaction mixture isbasified by treatment with aqueous potassium hydroxide solution (2 N)and extracted with dichloromethane (1500 mL). The organic layer isfiltered through diatomaceous earth, dried over magnesium sulpate, andconcentrated to give an off-white solid (13.72 g). This solid issubjected to mplc, using diethyl ether as eluent, to give4-amino-3,5-difluoropyridine (3.4 g), m.p. 99-101° C. [NMR (CDCl3):4.32(bs,2H),8.1(s,2H)].

REFERENCE EXAMPLE 75

By proceeding in a manner similar to that described in Reference Example3, but using the appropriate quantities of the corresponding carboxylicacids, there are prepared:

3-cyclopentylmethoxy-4-methoxybenzoyl chloride, in the form of a lightbrown oil;

3-cyclopropylmethoxy-4-methoxybenzoyl chloride, in the form of a lightbrown oil;

3-isopropoxy-4-methoxybenzoyl chloride, in the form of a golden oil;

3-tert-butoxy-4-methoxybenzoyl chloride in the form of a light brownoil; and

4-methoxy-3-(pent-3-yloxy)benzoyl chloride, in the form of a golden oil.

REFERENCE EXAMPLE 76

By proceeding in a manner similar to that described in Reference Example6, but using the appropriate quantities of the corresponding aldehydes,there are prepared:

3-cyclopentylmethoxy-4-methoxy-benzoic acid, in the form of a whitesolid, m.p. 148-152° C.;

3-cyclopropylmethoxy-4-methoxybenzoic acid, in the form of a whitesolid, m.p. 158-162° C.;

3-isopropoxy-4-methoxybenzoic acid, in the form of a white solid, m.p.133-135° C.; and

4-methoxy-3-(pent-3-yloxy)benzoic acid, in the form of a white solid,m.p. 137-139° C. [Elemental analysis: C,65.9; H,7.7%; calculated:C,65.5; H,7.6%].

REFERENCE EXAMPLE 77

A solution of methyl 3-tert-butoxy-4-methoxy benzoate (4.93 g) inmethanol (100 mL) is treated with a solution of potassium carbonate (3.5g) in water (40 mL), and the solution is stirred for 4 hours at reflux.The solution is evaporated to low volume, the residue is dissolved inwater (150 mL), washed with diethyl ether (100 mL) and brought to pH 4by treatment with glacial acetic acid. The resulting mixture isextracted with ethyl acetate (2×100 mL). The combined organic extractsare washed with water (50 mL), dried over magnesium sulfate, andconcentrated to give 3-tert-butoxy-4-methoxybenzoic acid (1.1 g) in theform of a white solid, m.p. 177-178° C. [NMR (CDCl3):7.88(dd,1H),7.76(d,1H), 6.94(d,1H),3.89(s,3H),1.39(s,9H)].

REFERENCE EXAMPLE 78

A stirred solution of 3-hydroxy-4-methoxy-benzaldehyde (5.74 g) in drydimethylformamide (50 mL) is treated with cyclopentylmethyl bromide(7.34 g) and potassium carbonate (15 g), and the solution is heated at60° C. for 24 hours. After cooling and filtration, the solution isevaporated to low bulk and dissolved in ethyl acetate (100 mL). Theorganic solution is washed with aqueous sodium hydroxide solution (4×50mL; 2 N) and water (2×50 mL), dried over magnesium sulfate, andevaporated to give 3-cyclopentyl-methoxy-4-methoxybenzaldehyde (6.5 g)in the form of a light brown oil.

By proceeding in a similar manner, but using the appropriate quantity ofisopropyl bromide, there is prepared 3-isopropoxy-4-methoxybenzaldehyde,in the form of a light golden oil. [NMR (CDCl3): 9.85(s,1H),7.46(dd,1H), 7.43(d,1H), 6.98(d,1H), 4.65(m,1H), 3.94(s,3H), 1.41(d,6H)].

REFERENCE EXAMPLE 79

By proceeding in a manner similar to that described in Reference Example1, but using the appropriate quantity of cyclopropylmethyl bromide,there is prepared 3-cyclopropylmethoxy-4-methoxy-benzaldehyde, m.p.55-58° C. [Elemental analysis: C,70.0; H,6.85%; calculated: C,69.9;H,6.8%].

By proceeding in a similar manner, but using the appropriate quantity of3-bromopentane, there is prepared4-methoxy-3-(pent-3-yloxy)benzaldehyde, in the form of a golden oil.

REFERENCE EXAMPLE 80

A stirred solution of isobutylene (33 mL) in dichloromethane (60 mL) at-70° C. is treated dropwise with a cooled solution of methyl3-hydroxy-4-methoxybenzoate (6 g) in dichloromethane (60 mL), followedby trifluoromethanesulfonic acid (0.3 mL). The reaction mixture isvigorously stirred at -70° C. for 3 hours and then between -70° C. and-50° C. overnight. It is then treated with triethylamine (0.6 mL) andallowed to warm to room temperature. The resulting yellow solution isconcentrated, and the residue is subjected by mplc, using diethyl etheras eluent, to give methyl 3-tert-butoxy-4-methoxybenzoate (4.93 g), m.p.98-100° C. [Elemental analysis: C,65.7; H,7.8%; calculated: C,65.5;H,7.6%].

REFERENCE EXAMPLE 81

A solution of3-[exobicyclo(2.2.1)hept-5-en-2-yloxy]-4-methoxy-benzaldehyde (8 g) andaqueous potassium hydroxide solution (1 mL; 50% w/v) in methanol (35mL), is stirred vigorously on an oil bath at 50° C. The mixture is thentreated, dropwise, with an aqueous solution of potassium hydroxide (8mL; 50% w/v) in methanol (35 mL) with hydrogen peroxide (21 mL; 35%w/v), to give a slightly exothermic reaction. The solution is stirredfor 2 hours at 50° C. and then is evaporated to low volume. The solutionis diluted with water (100 mL), adjusted to pH 5 by treatment withconcentrated hydrochloric acid and filtered to give3-[exobicyclo(2.2.1)-hept-5-en-2-yloxy]-4-methoxybenzoic acid (6.42 g),m.p. 161-163° C. [NMR (CDCl₃): 1.31(d,1H); 1.39(d,1H); 1.57(ddd,1H);1.65(d,1H); 2.68(bs,1H); 2.83(bs,1H); 3.67(s,3H); 4.09(d,1H);5.78(dd,1H); 6.06(dd,1H); 6.66(d,1H); 7.30(s,1H); 7.42(d,1H)].

REFERENCE EXAMPLE 82

Thionyl chloride (4 mL) is added to a solution of3-cyclopentyloxy-4-trifluoromethoxybenzoic acid (0.5 g) in dry toluene(10 mL) and the mixture is heated at 80° C. for 2 hours. Toluene isevaporated off under reduced pressure, to give3-cyclopentyloxy-4-trifluoro-methoxybenzoyl chloride (0.54 g), in theform of a yellow oil, which was used without further purification.

REFERENCE EXAMPLE 83

Potassium carbonate (0.43 g) and water (2 mL) are added to a solution ofmethyl 3-cyclopentyloxy-4-trifluoromethoxybenzoate (0.78 g) in methanol(10 mL) and the mixture is heated under reflux for 2 hours. Methanol isevaporated off under reduced pressure, and the crude material ispartitioned between water (75 mL) and ethyl acetate (75 mL). The organiclayer is separated, and the aqueous layer is acidified with hydrochloricacid (2 N) and extracted with ethyl acetate (2×75 mL). The combinedorganic extracts are dried over magnesium sulfate and evaporated underreduced pressure, to give 3-cyclopentyloxy-4-trifluoromethoxybenzoicacid (0.53 g), in the form of a white solid, m.p. 116-118° C. [NMR(CDCl₃): 7.72(d,1H,J=2 Hz); 7.7(dd,1H,J=8 Hz, 2 Hz); 7.3(d,1H,J=8Hz);4.9(m,1H);2.0-1.6(m,8H)].

REFERENCE EXAMPLE 84

Diisopropyl azodicarboxylate (0.61 mL) is added to a solution of methyl3-hydroxy-4-trifluoromethoxybenzoate (0.74 g), cyclopentanol (0.19 g)and triphenylphosphine (0.81 g) in tetrahydrofuran (10 mL) and themixture is heated overnight at reflux. Solvent is evaporated off underreduced pressure and the resulting yellow oil is triturated with diethylether. The white solid thus formed is filtered off, and the filtrate isevaporated under reduced pressure and subjected to mplc, to give methyl3-cyclopentyloxy-4-trifluoromethoxy-benzoate in the form of a paleyellow oil (0.6 g).

REFERENCE EXAMPLE 85

Methyl 3-amino-4-trifluoromethoxybenzoate (2.3 g) is dissolved in amixture of concentrated hydrochloric acid (5 mL) and water (10 mL), withslight warming. The solution is then cooled to -5° C. and a solution ofsodium nitrite (0.8 g) in water (2 mL) is added dropwise at thattemperature and the resulting yellow solution is stirred at 0° C. for 30minutes. A small amount of undissolved solid material is filtered off,and a solution of sodium tetrafluoroborate (1.52 g) in water (2 mL) isadded and the mixture is stirred at 0° C. for another 30 minutes. Thewhite solid thus formed is filtered off, washed with water and diethylether, and dried over phosphorus pentoxide under vacuum (yield=2.25 g).A portion (0.5 g) of this solid is then added to a solution of cupricnitrate (150 g) in water (100 mL). The mixture is extracted withdichloromethane (2×100 mL), and the extracts are dried over magnesiumsulfate and evaporated under reduced pressure, to give a pale yellowsolid (1.4 g), which is subjected to mplc, eluting with a mixture ofdiethyl ether and pentane (1:4 v/v), to give methyl3-hydroxy-4-trifluoromethoxybenzoate (1.0 g), in the form of a whitesolid, m.p. 95-97° C.

REFERENCE EXAMPLE 86

A solution of potassium carbonate (7.4 g) in water (72 mL) is added,dropwise, to a stirred solution of methyl3-(tetrahydrothiophen-3-oxy)-4-methoxybenzoate (11.8 g) in methanol (200mL) at room temperature. After the addition is complete, the solution isstirred and heated at 60-70° C. for 5 hours and allowed to stand at roomtemperature overnight. The solution is evaporated, the residue isdissolved in water, acidified with glacial acetic acid and theprecipitate formed is collected and dried, to give3-(tetrahydro-thiophen-3-oxy)-4-methoxybenzoic acid (7.4 g). m.p.177-179° C. [Elemental analysis: C,55.3; H,5.5; calculated: C,56.7;H,5.55%].

REFERENCE EXAMPLE 87

By proceeding as described in Reference Example 7, but using theappropriate quantities of 3-hydroxythiophane and isovanillic acid methylester, there was prepared methyl3-(tetrahydrothiophen-3-oxy)-4-methoxy-benzoate, in the form of a goldenoil. [Elemental analysis: C,55.2; H,6.8; S,8.1%; calculated: C,58.2;H,6.0; S,11.95%].

REFERENCE EXAMPLE 88

A solution of methyl3-(4,4-difluoro-3-methylenecyclobut-1-enyloxy)-4-methoxybenzoate (1.39g) in methanol (22 mL) is treated with a solution of potassium carbonate(0.83 g) in water (8 mL) and the solution is heated at 60-70° C. for 8hours, cooled and evaporated. The residue is dissolved in water (30 mL),extracted with diethyl ether (50 mL) and acidified to pH 4 by treatmentwith glacial acetic acid. The precipitated solid is extracted with ethylacetate (2×75 mL). The combined organic extracts are dried overmagnesium sulfate and concentrated, to give3-(4,4-difluoro-3-methylene-cyclobut-1-enyloxy)-4-methoxybenzoic acid,in the form of a white solid, m.p. 163-165° C.

REFERENCE EXAMPLE 89

A stirred solution of methyl 3-hydroxy-4-methoxybenzoate (1.72 g),potassium iodide (0.1 g), and potassium carbonate (1.55 g) indimethylformamide (50 mL) is treated with1-chloromethyl-2,2,3,3-tetrafluorocyclobutane (2.0 g), and the solutionis stirred at 70-80° C. for 6 hours. After cooling, the reaction mixtureis diluted with water (100 mL) and extracted with ethyl acetate (2×50mL). The organic extracts are combined, dried over magnesium sulfate andconcentrated, to give a golden oil. The oil is subjected to flashchromatography, using diethyl ether as eluent, to give methyl3-(4,4-difluoro-3-methylenecyclobut-1-enyloxy)-4-methoxybenzoate, m.p.60-62° C. [Elemental analysis: C,59.5; H,4.3%; calculated: C,52.2;H,4.4%].

REFERENCE EXAMPLE 90

By proceeding in a similar manner to Reference Example 6, but using3-(2-fluorocyclopentyloxy)-4-methoxybenzaldehyde as the startingmaterial, there is prepared 3-(2-fluorocyclopentyloxy)-4-methoxybenzoicacid. Mass spectrum m/z 254(M⁺).

REFERENCE EXAMPLE 91

By proceeding in a similar manner to Reference Example 7, but using2-trans-fluorocyclopentanol as the starting material, there is prepared3-(2-fluorocyclopentyloxy)-4-methoxybenzaldehyde. Mass spectrum m/z238(M⁺).

REFERENCE EXAMPLE 92

By proceeding in a manner similar to that described in Reference Example20, but using as the starting material the appropriate quantity of3-isopropoxy-4-(methylthio)benzoic acid, there is prepared3-isopropoxy-4-(methylthio)benzoyl chloride, in the form of a yellowoil.

REFERENCE EXAMPLE 93

By proceeding in a manner similar to that described in Reference Example19, but using as the starting material the appropriate quantity ofmethyl 3-isopropoxy-4-(methylthio)benzoate, there is prepared3-isopropoxy-4-(methylthio)benzoic acid, in the form of a white solid,m.p. 127-129° C. [Elemental analysis: C,58.5; H,6.3; S,14.5%;calculated: C,58.4; H,6.2; S,14.2%].

REFERENCE EXAMPLE 94

A solution of methyl 3-isopropoxy-4-nitrobenzoate (5.7 g) inN,N'-dimethylimidazolidinone (35 mL) is treated with sodiumthiomethoxide (2 g), and the mixture is stirred at room temperature for4 hours. The mixture is then diluted with water (250 mL) containingsodium chloride (47 g), and is extracted with ethyl acetate (2×100 mL).The combined organic extracts are washed with brine (100 mL), dried overmagnesium sulfate and evaporated in vacuo, to give a brown oil. The oilis subjected to flash chromatography, eluting with a 1.9 v/v mixture ofdiethyl ether and pentane, to give methyl3-isopropoxy-4-(methylthio)benzoate (4.0 g), in the form of a creamsolid, m.p. 41-43° C.

REFERENCE EXAMPLE 95

A solution of methyl 3-hydroxy-4-nitrobenzoate (5.9 g) indimethylformamide (40 mL) is treated with potassium carbonate (6.2 g)and 2-bromopropane (3.7 g), and the stirred solution is heated at 60-65°C. for 4 hours. After cooling, water (100 mL) is added and the solutionis extracted with toluene (2×100 mL) The combined organic extracts aredried over magnesium sulfate and evaporated in vacuo, to give methyl3-isopropoxy-4-nitrobenzoate, in the form of a pale yellow solid (5.9g), m.p. 46-48° C.

REFERENCE EXAMPLE 96

By proceeding in a manner similar to that described in Reference Example63, but using as the starting material the appropriate quantity of(±)-3-[(exo)-8,9,10-trinorbornyl-2-oxy]-4-methoxybenzaldehyde, there isprepared, after flash chromatography, eluting with a mixture of ethylacetate and pentane (1:2v/v),rac-1-[3-{(exo)-8,9,10-trinorbornyl-2-oxy}-4-methoxyphenyl]-2-(3,5-dichloropyrid-4-yl)ethanone,in the form of a yellow oil.

REFERENCE EXAMPLE 97

By proceeding in a manner similar to that described in Reference Example63, but using as the starting material the appropriate quantity of3-cyclopentyloxy-4-(methylthio)benzaldehyde, there is prepared1-[3-cyclo-pentyloxy-4-(methylthiophenyl)-2-(3,5-dichloropyrid-4-yl)ethanol,in the form of a white solid, m.p. 122-123° C. [Elemental analysis:C,57.3; H,5.3; Cl,17.6; N,3.4; S,8.4%; calculated: C,57.3; H,5.3;Cl,17.8; N,3.5; S,8.1%].

REFERENCE EXAMPLE 98

A solution of 4-bromo-2-cyclopentyloxy-1-(methylthio)benzene (13.2 g) indry tetrahydrofuran (100 mL) under nitrogen is treated at -70° C. with asolution of butyllithium in hexane (20.24 mL; 2.5 M) and the resultingsolution is stirred for 1 hour at this temperature. It is then treatedwith dimethylformamide (7.12 mL), followed by boron trifluoride diethyletherate (11.32 mL), keeping the temperature at -65° C. When theaddition is complete the reaction mixture is allowed to warm to roomtemperature and is then poured into ice-water (450 mL) and extractedwith dichloromethane (3×400 mL). The combined extracts are dried overmagnesium sulfate and concentrated to give an oil, which is subjected toflash chromatography, eluting with a mixture of dichloromethane andcyclohexane (3:7 v/v), to give3-cyclopentyloxy-4-(methylthio)-benzaldehyde (6.2 g). [NMR (DMSO):9.91(S,1H),7.53(dd,1H),7.36(d,1H), 7.33(d,1H),5.01(m,1H),2.44(s,3H),2.0-1.5(m,8H)].

REFERENCE EXAMPLE 99

A stirred solution of 4-bromo-2-hydroxythioanisole (15.9 g) andcyclopentyl bromide (16.05 g) in dry dimethylformamide (170 mL,) istreated with anhydrous potassium carbonate (14.7 g) and the mixture isheated at 60° C. for 1 day. After cooling, the solution is diluted withwater (250 mL) and extracted with ethyl acetate (3×100 mL). The combinedextracts are dried over magnesium sulfate and concentrated. The residueis subjected to flash chromatography, eluting with a mixture of ethylacetate and pentane (5:95 v/v), to give4-bromo-2-cyclopentyloxy-1-(methylthio)benzene, in the form of an oil(17.2 g). [NMR (DMSO): 7.14-7.03(m,3H),4.93(m,1H),2.33(s,3H),2.0-1.53(m,8H)].

REFERENCE EXAMPLE 100

By proceeding in a manner similar to that described in Reference Example63, but using as the starting material the appropriate quantity of4-methoxy-3-prop-2-yloxybenzaldehyde, there is prepared1-(4-methoxy-3-prop-2-yloxyphenyl)-2-(3,5-dichloropyrid-4-yl)ethanol, inthe form of a buff solid, m.p. 132-133° C. [Elemental analysis: C,57.2;H,5.37; Cl,19.8; N,3.80%; calculated: C,57.32; H,5.38; Cl,19.9;N,3.93%].

REFERENCE EXAMPLE 101

A mixture of 3-hydroxy-4-methoxybenzaldehyde (20.0 g), anhydrouspotassium carbonate (26.2 g) and 2-bromopropane (18.3 mL) in drydimethylformamide (300 mL) is stirred and heated at 55-65° C. for 24hours. The cooled mixture is poured into water and extracted with ethylacetate. The extract is dried over magnesium sulfate and concentrated invacuo at 40° C., to give 4-methoxy-3-prop-2-yloxybenzaldehyde, in theform of an oil (24.2 g).

REFERENCE EXAMPLE 102

By proceeding in a manner similar to that described in Example 63, butusing as the starting material the appropriate quantity of4-methylthio-3-prop-2-yloxybenzaldehyde, there is prepared1-(4-methylthio-3-prop-2-yloxyphenyl)-2-(3,5-dichloropyrid-4-yl)ethanol,in the form of a buff solid, m.p. 106-108° C. [Elemental analysis:C,55.1; H,5.23; N,3.73%; calculated: C,54.84; H,5.14; N,3.76%].

REFERENCE EXAMPLE 103

A solution of n-butyllithium in hexanes (14.82 mL; 2.5M) is added to asolution of 4-bromo-2-prop-2-yloxythioanisole (8.8 g) in drytetrahydrofuran (70 mL), whilst cooling the mixture to -70° C. undernitrogen. The mixture is stirred for 1 hour at -70° C. Drydimethylformamide (5.22 mL) and boron trifluoride diethyl etherate (8.29mL) are added sequentially and the mixture is allowed to warm to roomtemperature. The mixture is poured into water and the product isextracted with dichloromethane. The extract is dried over magnesiumsulfate and concentrated in vacuo, and the residue is subjected to flashchromatography on silica gel, eluting with a mixture of pentane andethyl acetate (9:1 v/v) to give 4-methylthio-3-prop-2-yloxybenzaldehyde,in the form of a soft yellow solid, m.p. 50-54° C.

REFERENCE EXAMPLE 104

By proceeding in a manner similar to that described in Reference Example99, but using as the starting material the appropriate quantity of2-bromopropane, there is prepared 4-bromo-2-prop-2-yloxythioanisole, inthe form of a colourless oil.

REFERENCE EXAMPLE 105

By proceeding in a manner similar to that described in Reference Example63, but using as the starting material the appropriate quantity of3-cyclopentyloxy-4-difluoromethoxybenzaldehyde, there is prepared1-(3-cyclopentyloxy-4-difluoromethoxyphenyl)-2-(3,5-dichloropyrid-4-yl)ethanol,in the form of a pale yellow solid, m.p. 121-123° C. [Elementalanalysis: C,55.2; H,4.6; N,3.3; Cl,16.7%; calculated: C,54.6; H,4.6;N,3.35; Cl,16.95%].

REFERENCE EXAMPLE 106

A solution of 3-cyclopentyloxy-4-hydroxybenzaldehyde (5.1 g) indimethylformamide (50 mL) is treated with potassium carbonate (4.83 g)and potassium iodide (1.2 g) and the solution is heated at 70-75° C.whilst difluorochloromethane is bubbled though it at a slow rate, during5 hours. Water (100 mL) is added and the mixture is extracted with ethylacetate (2×100 mL). The combined organic extracts are dried overmagnesium sulfate and concentrated to give a brown oil. The oil issubjected to flash chromatography, eluting with a mixture of diethylether and pentane (1:4 v/v), to give3-cyclopentyloxy-4-difluoromethoxybenzaldehyde, in the form of a paleyellow oil (4.7 g). [NMR (CDCl₃): 9.92(s,1H); 7.5-7.24(m,3H);6.34-5.96(t,1H); 4.9(m,1H); 2.0-1.6(m,8H)].

REFERENCE EXAMPLE 107

By proceeding in a manner similar to that described in Reference Example63, but using as the starting material the appropriate quantity of3-[exobicyclo(2.2.1)hept-5-en-2-yloxy]-4-methoxy-benzaldehyde, there isprepared2-(3,5-dichloropyrid-4-yl)-1-[3-{exobicyclo(2.2.1)hept-5-en-2-yloxy}-4-methoxyphenyl]ethanol.[NMR (CDCl₃): 1.2-1.4(m,1H); 1.45-1.6(m,1H); 1.65-1.8(m,1H); 1.9(m,1H);2.1(bs,1H); 2.9(bs,1H); 3.05(bd,J=14 Hz,1H); 3.25(dd,J=5 Hz,J=12 Hz,1H);3.4-3.5(m,1H); 3.84(s,3H); 4.28(bm,1H); 5.05(m,1H); 6.02(m,1H);6.3(m,1H); 6.8-6.95(m,3H),8.42(s,2H)].

REFERENCE EXAMPLE 108

By proceeding in a manner similar to that described in Example 63, butusing as the starting material the appropriate quantity of4-difluoromethoxy)-3-isopropoxybenzaldehyde there is prepared2-(3,5-dichloro-4-pyridyl)-1-(4-difluoromethoxy-3-isopropoxyphenyl)-ethanol,in the form of a white solid, m.p. 125-126° C. [Elemental analysis:C,52.3; H,4.4; N,3.5; Cl,18.1%; calculated: C,52.1; H,4.4; N,3.6;Cl,18.1%].

REFERENCE EXAMPLE 109

A cold (0° C.) solution of 4-hydroxymethyl-3,5-dichloropyridine (3.0 g)and N-bromosuccinimide (6.1 g) in dry dimethylformamide (100 mL) istreated with triphenylphosphine (8.9 g), portionwise, during 5 minutes.The resulting red solution is stirred at 0° C. for 45 minutes, and thentreated with methanol (5 mL), followed by water (300 mL). The mixture isextracted with diethyl ether (4×200 mL), the combined organic washingsdried over sodium sulfate, and the solvent removed under reducedpressure. The resulting residue is chromatographed on silica gel,eluting with a mixture of diethyl ether and pentane (1:2 v/v), to give4-bromomethyl-3,5-dichloropyridine (3 g), in the form of an off-whitesolid, m.p. 40-44° C.

REFERENCE EXAMPLE 110

A cold (0° C.) solution of 4-formyl-3,5-dichloro-pyridine (3.0 g) inethanol (50 mL) is treated with sodium borohydride (0.7 g), portionwise,during 5 minutes. The resulting mixture is stirred at 0° C. for 10minutes, and then treated with aqueous hydrochloric acid (5 mL; 2 M),followed by basification to pH 7 by treatment with saturated aqueoussodium hydrogen carbonate solution. The mixture is diluted with water(500 mL) and extracted with ethyl acetate (4×150 mL). The combinedorganic washings are dried over magnesium sulfate, and the solventremoved under reduced pressure. The resulting residue is recrystallisedfrom t-butyl methyl ether to give 4-hydroxymethyl-3,5-dichloropyridine(2.0 g), in the form of a white solid, m.p. 87-88° C.

REFERENCE EXAMPLE 111

By proceeding in a manner similar to that described in Reference Example62, but using instead of methyl iodide the appropriate quantity ofdimethylformamide, there is prepared 4-formyl-3,5-dichloropyridine, inthe form of an off-white solid, m.p. 73-75° C.

The compounds of formula I exhibit useful pharmacological activity andaccordingly are incorporated into pharmaceutical compositions and usedin the treatment of patients suffering from certain medical disorders.More especially, they are cyclic AMP phosphodiesterase inhibitors, inparticular type IV cyclic AMP phosphodiesterase inhibitors. The presentinvention provides compounds of formula I, and compositions containingcompounds of formula I, which are of use in a method for the treatmentof a patient suffering from, or subject to, conditions which can beameliorated by the administration of an inhibitor of cyclic AMPphosphodiesterase. For example, compounds within the present inventionare useful as bronchodilators and asthma-prophylactic agents and agentsfor the inhibition of eosinophil accumulation and of the function ofeosinophils, e.g. for the treatment of inflammatory airways disease,especially reversible airway obstruction or asthma, and for thetreatment of other diseases and conditions characterized by, or havingan etiology involving, morbid eosinophil accumulation. As furtherexamples of conditions which can be ameliorated by the administration ofinhibitors of cyclic AMP phosphodiesterase such as compounds of formulaI there may be mentioned inflammatory diseases, such as atopicdermatitis, urticaria, allergic rhinitis, psoriasis, rheumaticarthritis, ulcerative colitis, Crohn's disease, adult respiratorydistress syndrome and diabetes insipidus, other proliferative skindiseases such as keratosis and various types of dermatitis, conditionsassociated with cerebral metabolic inhibition, such as cerebralsenility, multi-infarct dementia, senile dementia (Alzheimer's disease),and memory impairment associated with Parkinson's disease, andconditions ameliorated by neuroprotectant activity, such as cardiacarrest, stroke, and intermittent claudication. A special embodiment ofthe therapeutic methods of the present invention is the treating ofasthma.

The compounds are also inhibitors of tumor necrosis factor, especiallya-TNF. Thus, the present invention provides compounds of formula I, andcompositions containing compounds of formula I, which are of use in amethod for treating a patient suffering from, or subject to, conditionswhich can be ameliorated by the administration of an inhibitor of a-TNF.For example compounds of the present invention are useful in jointinflammation, arthritis rheumatoid arthritis and other arthriticconditions such as rheumatoid spondylitis and osteoarthritis.Additionally, the compounds are useful in treatment of sepsis, septicshock, gram negative sepsis, toxic shock syndrome, acute respiratorydistress syndrome, asthma and other chronic pulmonary diseases, boneresorption diseases, reperfusion injury, graft vs. host reaction andallograft rejection. Furthermore, the compounds are useful in thetreatment of infections such as viral infections and parasiticinfections, for example malaria such as cerebral malaria, fever andmyalgias due to infection, HIV, AIDS, cachexia such as cachexiasecondary to AIDS or to cancer. Other disease states that may be treatedwith the compounds of the present invention include Crohn's disease,ulcerative colitis, pyresis, systemic lupus erythematosus, multiplesclerosis, type I diabetes mellitus, psoriasis, Bechet's disease,anaphylactoid purpura nephritis, chronic glomerilonephritis,inflammatory bowel disease and leukemia. A special embodiment of thetherapeutic methods of the present invention is the treating ofjointinflammation.

According to a further feature of the invention there is provided amethod for the treatment of a human or animal patient suffering from, orsubject to, conditions which can be ameliorated by the administration ofan inhibitor of cyclic AMP phosphodiesterase or of TNF, especiallya-TNF, for example conditions as hereinbefore described, which comprisesthe administration to the patient of an effective amount of compound offormula I or a composition containing a compound of formula I."Effective amount" is meant to describe an amount of compound of thepresent invention effective in inhibiting cyclic AMP phosphodiesteraseand/or TNF and thus producing the desired therapeutic effect.

The present invention also includes within its scope pharmaceuticalformulations which comprise at least one of the compounds of formula Iin association with a pharmaceutically acceptable carrier or coating.

In practice compounds of the present invention may generally beadministered parenterally, rectally or orally, but they are preferablyadministered by inhalation.

The products according to the invention may be presented in formspermitting administration by the most suitable route and the inventionalso relates to pharmaceutical compositions containing at least oneproduct according to the invention which are suitable for use in humanor veterinary medicine. These compositions may be prepared according tothe customary methods, using one or more pharmaceutically acceptableadjuvants or excipients. The adjuvants comprise, inter alia, diluents,sterile aqueous media and the various non-toxic organic solvents. Thecompositions may be presented in the form of tablets, pills, granules,powders, aqueous solutions or suspensions, injectable solutions, elixirsor syrups, and can contain one or more agents chosen from the groupcomprising sweeteners, flavorings, colorings, or stabilizers in order toobtain pharmaceutically acceptable preparations.

The choice of vehicle and the content of active substance in the vehicleare generally determined in accordance with the solubility and chemicalproperties of the product, the particular mode of administration and theprovisions to be observed in pharmaceutical practice. For example,excipients such as lactose, sodium citrate, calcium carbonate, dicalciumphosphate and disintegrating agents such as starch, alginic acids andcertain complex silicates combined with lubricants such as magnesiumstearate, sodium lauryl sulfate and talc may be used for preparingtablets. To prepare a capsule, it is advantageous to use lactose andhigh molecular weight polyethylene glycols. When aqueous suspensions areused they can contain emulsifying agents or agents which facilitatesuspension. Diluents such as sucrose, ethanol, polyethylene glycol,propylene glycol, glycerol and chloroform or mixtures thereof may alsobe used.

For parenteral administration, emulsions, suspensions or solutions ofthe products according to the invention in vegetable oil, for examplesesame oil, groundnut oil or olive oil, or aqueous-organic solutionssuch as water and propylene glycol, injectable organic esters such asethyl oleate, as well as sterile aqueous solutions of thepharmaceutically acceptable salts, are used. The solutions of the saltsof the products according to the invention are especially useful foradministration by intramuscular or subcutaneous injection. The aqueoussolutions, also comprising solutions of the salts in pure distilledwater, may be used for intravenous administration with the proviso thattheir pH is suitably adjusted, that they are judiciously buffered andrendered isotonic with a sufficient quantity of glucose or sodiumchloride and that they are sterilized by heating, irradiation ormicrofiltration.

Suitable compositions containing the compounds of the invention may beprepared by conventional means. For example, compounds of the inventionmay be dissolved or suspended in a suitable carrier for use in anebulizer or a suspension or solution aerosol, or may be absorbed oradsorbed onto a suitable solid carrier for use in a dry powder inhaler.

Solid compositions for rectal administration include suppositoriesformulated in accordance with known methods and containing at least onecompound of formula I.

The percentage of active ingredient in the compositions of the inventionmay be varied, it being necessary that it should constitute a proportionsuch that a suitable dosage shall be obtained. Obviously, several unitdosage forms may be administered at about the same time. The doseemployed will be determined by the physician, and depends upon thedesired therapeutic effect, the route of administration and the durationof the treatment, and the condition of the patient. In the adult, thedoses are generally from about 0.001 to about 50, preferably about 0.001to about 5, mg/kg body weight per day by inhalation, from about 0.01 toabout 100, preferably 0.1 to 70, more especially 0.5 to 10, mg/kg bodyweight per day by oral administration, and from about 0.001 to about 10,preferably 0.01 to 1, mg/kg body weight per day by intravenousadministration. In each particular case, the doses will be determined inaccordance with the factors distinctive to the subject to be treated,such as age, weight, general state of health and other characteristicswhich can influence the efficacy of the medicinal product.

The products according to the invention may be administered asfrequently as necessary in order to obtain the desired therapeuticeffect. Some patients may respond rapidly to a higher or lower dose andmay find much weaker maintenance doses adequate. For other patients, itmay be necessary to have long-term treatments at the rate of 1 to 4doses per day, in accordance with the physiological requirements of eachparticular patient. Generally, the active product may be administeredorally 1 to 4 times per day. It goes without saying that, for otherpatients, it will be necessary to prescribe not more than one or twodoses per day.

Compounds within the scope of the present invention exhibit markedpharmacological activities according to tests described in theliterature which tests results are believed to correlate topharmacological activity in humans and other mammals. The followingpharmacological test results are typical characteristics of compounds ofthe present invention.

1. Inhibitory Effects of Compounds on PDE Activity.

1.1 Preparation of PDE Isozymes from Pig Aorta.

The method is described fully by Souness and Scott (Biochem. J., 291,389-395,1993). Briefly, aortas of freshly slaughtered pigs are placed inHepes buffered krebs solution extraneous tissue on the outside of theaorta is trimmed off and the endothelial layer on the intimal surface isremoved by rubbing with a cotton swab. Smooth muscle strips are pluckedfrom the aorta and 25 g are homogenized using a Waring Blender inhomogenization buffer (20 mM Tris/HCl, pH 7.5, 2 mM MgCl₂, 1 mMdithiothreitol, 5 mM EDTA and 1 mg/ml aprotinin). The homogenate isfurther homogenized with an Ultra-Turrax and then centrifuged (3000 g, 5minutes). The supernatant is removed, and the pellet is sonicated in asmall volume (25-50 mL) of homogenization buffer. The sonicate iscentrifuged (3000 g, 5 minutes), the pellet discarded and thesupernatant is pooled with that from the first centrifugation step. Thepooled supernatants are centrifuged (100,000 g, 1 hour), the resultinghigh-speed supernatant is filtered (0.45 μm) and then applied to aDEAE-trisacryl (IBF) column (50×2.44 cm) preequilibrated in columnbuffer (20 mM Tris/HCl, pH 7.5, 2 mM MgCl₂, 1 mM dithiothreitol, 20 μMTLCK). The column is washed with 500-700 mL of column buffer and PDEactivities are eluted with 2 successive linear gradients of NaCl (0-200mM, 400 mL and 200-300 mM, 200 mL) in column buffer. The fractions inthe separated peaks of activity corresponding to the different PDEisozymes are pooled and stored at -20° C. in 30% (v/v) ethylene glycol.

1.2 Measurement of PDE Activity.

PDE activity is determined by the two-step radioisotopic method ofThompson et al., Adv. Cyclic Nucl. Res., 10, 69-92 (1979). The reactionmixture contains 20 mM Tris/HCl (pH 8.0), 10 mM MgCl₂, 4 mM2-mercaptoethanol, 0.2 mM EGTA and 0.05 mg of BSA/mL. The concentrationof substrate is 1 μM.

The IC₅₀ values for the compounds examined are determined fromconcentration-response curves in which concentrations range from 0.1 nMto 40 μM.

1.3 Results.

Compounds within the scope of the invention produce up to about 50%inhibition of porcine aortic cyclic AMP-specific phosphodiesterase (PDEIV) at concentrations from about 10⁻⁹ M up to about 10⁻⁵ M, preferablyfrom about 10⁻⁹ up to about 10⁻⁸ M. The compounds of the invention arefrom about 10,000-fold to about 50-fold more selective for cyclic AMPphosphodiesterase IV than cyclic nucleotide phosphodiesterase types I,III or V.

2. Inhibitory Effects of Compounds on Eosinophil Superoxide Generation.

2.1 Preparation of Guinea-pig Eosinophils.

The method is described fully in Souness et al (Biochem. Pharmacol. 42,937-945, 1991).

2.2 Measurement of Superoxide Generation.

Superoxide anion generation is determined as the superoxide dismutaseinhibitable reduction of p-iodonitrotetrazolium violet (INTV) (Sounesset al, Biochem. Pharmacol. 42, 937-945, 1991). Briefly, cells areincubated in 96 well microtitre plates in 0.25 mL of Hanks buffered saltsolution (HBSS) containing INTV (0.5 mg/mL) plus other additions for 45minutes at 37° C. The cells are then centrifuged at 500 g for 5 minutesand the supernatant is aspirated. The pellet is solubilized byincubation overnight at room temperature in DMSO containing 0.6M HCl andthe absorbance of the reduced dye is measured at 492 nm. The results areexpressed in absorbance units.

2.3 Results.

Compounds within the scope of the invention produce up to about 50%inhibition of superoxide generation from eosinophiis harvested from theperitoneal cavities of guinea-pigs at concentrations from about 10⁻⁸ Mto about 10⁻⁵ M, preferably from about 10⁻⁸ M up to about 10⁻⁷ M.

3. Effects of Compounds on Tracheal Smooth Muscle Contractility.

3.1 Preparation of Guinea-pig Tracheal Strips and Contractility Studies.

Organ bath studies are performed essentially according to Tomkinson etal (Br. J. Pharmacol. 108 57-61, 1993). Briefly, tracheas are removedfrom male, Dunkin-Hartley guinea-pigs (400-500 g) are placed in KrebsRinger Bicarbonate (KRB) solution and fat and connective tissue aredissected away. Epithelium is removed by mechanical abrasion and thetracheal strips are suspended under an applied load, such that they areat their optimal length, derived from preliminary experiments, andequilibrated for 90 minutes, washing at 15 minute intervals.

Cumulative concentration-response curves to spasmogens are constructedand the concentration producing 30% of maximum contraction (EC₃₀) isdetermined by computerized linear regression analysis. For relaxantstudies, tissues are contracted with spasmogens (such as methacholine,histamine, leukotriene D₄) (EC₃₀) and when the response plateaus, PDEinhibitors (10 nM-100 μM) or vehicle control (DMSO) are addedcumulatively. The concentration of relaxant producing 50% inhibition(IC₅₀) of the agonist response is calculated by linear regression.Alternatively, PDE inhibitors, as above, may be added to tissues underbasal tone and the concentration producing 50% relaxation (EC₅₀)calculated as above.

3.2 Results.

Compounds within the scope of the invention produce about 50% relaxationof guinea-pig tracheal strips (under basal tone or which had beencontracted by treatment with spasmogens) at concentrations from about5×10⁻⁹ M to about 10⁻⁵ M, preferably from about 5×10⁻⁹ M to about 10⁻⁷M.

4. In vivo Bronchodilator Actions of Compounds.

4.1 Measurement of Bronchodilatation.

Bronchorelaxant activity is measured in in vivo tests in theanaesthetized guinea-pig or rat according to the method described inUnderwood et al. Pulm. Pharmacol. 5, 203-212, (1992) in which theeffects on bronchospasm induced by histamine (or other spasmogens suchas methacholine or leukotriene D₄) is determined. Nebulized aerosolsgenerated from aqueous solutions of compounds of the invention are eachadministered for one minute to the anaesthetized animals. Alternatively,dry powder formulations made up from compounds of the invention andlactose are blown into the airways of the anaesthetized guinea-pigs orrats by the method described in Underwood et al., J. Pharm. Methods, 26,203-210, 1991.

4.2 Results.

Compounds within the scope of the invention produce from about 30% up toabout 90% decrease in bronchospasm when administered at effective dosesof about 4 to about 1000 μg/kg, preferably about 4 to about 50 μg/kg,without any significant effect on blood pressure.

5. In vivo Actions of Compounds on Antigen (ovalbamin)-inducedEosinophilia in Guinea-pigs.

5.1 Treatment of Animals and Measurement of Eosinophil Numbers.

Male Dunkin-Hartley guinea-pigs weighing 200-250 g are sensitized using10 μg ovalbumin in 1 mL of a 100 mg/mL suspension of aluminiumhydroxide, i.p.

Sensitized guinea-pigs are anaesthetised and dry powder formulations ofPDE inhibitors or lactose are administered (i.t.) into the airways. Insome cases PDE inhibitors are administered orally. 23 hours later theprocedure is repeated and 60 minutes later the guinea-pigs arechallenged with nebulised saline or ovalbumin (1% in saline) for 15seconds. 24 hours after challenge the guinea-pigs are killed and thelungs are lavaged with warm saline. Total and differential cell countsare made.

5.2 Results.

Compounds within the scope of the invention, administered one hourbefore challenge, inhibit by at least 50% ovalbumin-induced eosinophiliain guinea-pigs which is measured 24 hours after challenge, at oral dosesof about 1 to about 50 mg/kg, preferably about 1 to 10 mg/kg and inhaleddoses of about 4 to 1000 μg/kg, preferably 0.4 to 50 μg/kg.

6 In Vitro Inhibitory Effects on TNF-a Release by Human Monocytes.

The effects of compounds on TNF-a production by human peripheral bloodmonocytes (PBMs) are examined as follows:

6.1. Preparation of Blood Leukocytes.

Blood is drawn from normal donors, mixed with dextran, and theerythrocytes allowed to sediment for 35 minutes at 37° C. Leukocytes arefractionated by centrifugation through a discontinuous (18, 20 and 22%)metrizamide gradient. The mononuclear cell fraction comprising 30-40%PBMs is suspended in HBSS and stored at 4° C. until use.

6.2. Measurement of TNFa.

Cells from the PBM-rich metrizamide fraction are spun down (200 g for 10minutes at 20° C.), resuspended at 10⁶ PBMs/mL of medium; RPMI 1640containing 1l% v/v FCS, 50 U/mL penicillin and 50 mg/mL streptomycin(Gibco, U.K.), then plated out in 96 well plates at 2×10⁵ cells/well.The medium (200 L) is changed to remove any non-adherent cells and theremaining, adherent PBMs left in the incubator overnight (18 hours). Onehour prior to challenge, the medium is changed to that containingcompound for test or drug vehicle. Control treatments and compounds fortest are assayed in quadruplicate wells. Compounds are tested within theconcentration range of 3×10⁻¹⁰ M to 3×10⁻⁶ M. Medium (50 PL) with orwithout 10 ng/ml LPS (E. Coli, 055 B5 from Sigma, U.K.) is then added.The incubation is then continued for a further 4 hours. Cellsupernatants are removed for storage at -20° C.

TNFa levels in cell supernatants are quantified using a standardsandwich ELISA technique. ELISA plates (Costar, U.K.) are coatedovernight at 4° C. with 3 mg/mL polyclonal goat anti-human TNFa antibody(British Biotechnology, U.K.) in pH 9.9 bicarbonate buffer. Rabbitpolyclonal anti-human TNFa antiserum (Janssen Biochimicha, Belgium) at1/500 dilution is used as the second antibody and polyclonal goatanti-rabbit IgG horseradish peroxidase (Calbiochem, U.S.A.) at 1/8000dilution is used as the detection antibody. Color development ismeasured by absorbance at 450 nm using a Titertek plate reader.

TNF-a levels are calculated by interpolation from a standard curve usingrecombinant human TNF-a (British Biotechnology U.K.)(0.125-8 ng/mL).Data (log-conc. vs. log-resp) are fitted by linear regression (p>0.99)using a Multicalc (Wallac Pharmacia, U.K.) software program. Basal TNF-alevels are less than 100 pg/mL whilst LPS stimulation of the PBMsincreases TNF-a levels to 3-10 ng/mL.

6.3 Results.

Compounds within the scope of the invention produce 50% inhibition ofLPS-induced TNF-a release from human PBMs at concentrations within therange of about 10⁻⁹ M to about 10⁻⁶ M., preferably about 10⁻⁹ M to about10⁻⁸ M.

7. Inhibitory Effects of Compounds on Antigen-inducedBronchoconstriction in the Conscious Guinea-pig.

7.1. Sensitisation of Guinea-pigs and Measurement of Antigen--inducedBronchoconstriction.

Male, Dunkin-Hartley guinea-pigs (550-700 g) are sensitized as above.Specific airways resistance (SRaw) is measured in conscious animals bywhole body plethysmography using a variation of the method of Pennock etal., (J. Appl. Physiol., 46,399, 1979). Test compounds or vehicle(lactose carrier) are instilled into the airways as dry powders througha metal gavage needle. 30 minutes later, the animals are injected withmepyramine (30 mg/kg i.p.) to prevent anaphylactic collapse and placedinto the plethysmography chambers where SRaw is determined at 1 minuteintervals. Resting SRaw is then determined. Animals are challenged withan aerosol of ovalbumin and SRaw is determined every 5 minutes for 15minutes.

7.2. Results.

Compounds within the scope of the invention inhibit antigen-inducedbronchoconstriction by up to 80% at doses of between about 1 to about1000 μg/kg (i.t.), preferably about 1 to about 20 μg/kg (i.t.).

8. Inhibitory effects of compounds on serum TNF-a levels inLPS--challenged mice.

8.1. Treatment of Animals and Measurement of Murine TNF-a.

Female Balb/c mice (age 6-8 weeks, weight 20-22 g from Charles River,U.K.) in groups of five or more animals are dosed p.o. with compoundssuspended in 1.5% (w/v) carboxymethyl cellulose then challenged after aminimum period of 30 min with 30 mg of LPS i.p. After 90 min the animalsare killed by CO₂ asphyxiation and bled by cardiac puncture. Blood isallowed to clot at 4° C., centrifuged (12,000 g for 5 minutes) and serumtaken for TNF-a analysis.

TNF-a levels are measured using a commercially available murine TNF-aELISA kit, purchased from Genzyme (Cat. no. 1509.00), as recommended bythe manufacturer. Values for TNF-a are calculated from a recombinantmurine TNF-a standard curve.

8.2 Results.

Compounds within the scope of the invention inhibit LPS-induced serumTNF-a at doses between about 10 and about 10,000 mg/kg, preferably about10 to about 250 μg/kg.

The value of the compounds of the invention is enhanced by their verylow mammalian toxicity levels.

The following Composition Examples illustrate pharmaceuticalcompositions according to the present invention.

COMPOSITION EXAMPLE 1

N-(2,6-Difluorophenyl)-3-cyclopentyloxy-4-methoxybenzamide (1 g) (meanparticle size 3.5 microns) and lactose (99 g) (mean particle size 72microns) were blended together for 30 minutes in a mechanicalshaker/mixer. The resulting blend was filled, to a fill weight of 25 mg,into No. 3 hard gelatin capsules, to give a product suitable for use,for example, with a dry powder inhaler.

COMPOSITION EXAMPLE 2

N-(3,5-Dichloropyrid-4-yl)-3-cyclopentyloxy-4-methoxybenzamide (1 g)(mean particle size 3.5 microns) and lactose (99 g) (mean particle size72 microns) are blended together for 30 minutes in a mechanicalshaker/mixer. The resulting blend is filled, to a fill weight of 25 mg,into No. 3 hard gelatin capsules, to give a product suitable for use,for example, with a dry powder inhaler.

COMPOSITION EXAMPLE 3

    ______________________________________                                        No. 2 size gelatin capsules each containing:                                  ______________________________________                                        N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-                                                            20     mg                                           4-methoxybenzamide                                                            lactose                   100    mg                                           starch                    60     mg                                           dextrin                   40     mg                                           magnesium stearate        1      mg                                           ______________________________________                                    

are prepared in accordance with the usual procedure.

COMPOSITION EXAMPLE 4

N-(3,5-Dichloropyrid-4-yl)-3-cyclopentyloxy-4-(methylthio)benzamide (1g) (mean particle size 3.5 microns) and lactose (99 g) (mean particlesize 72 microns) are blended together for 30 minutes in a mechanicalshaker/mixer. The resulting blend is filled, to a fill weight of 25 mg,into No. 3 hard gelatin capsules, to give a product suitable for use,for example, with a dry powder inhaler.

COMPOSITION EXAMPLE 5

    ______________________________________                                        No. 2 size gelatin capsules each containing:                                  ______________________________________                                        N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-                                                            20     mg                                           4-(methylthio)benzamide                                                       lactose                   100    mg                                           starch                    60     mg                                           dextrin                   40     mg                                           magnesium stearate        1      mg                                           ______________________________________                                    

are prepared in accordance with the usual procedure.

COMPOSITION EXAMPLE 6

(±)-N-(3,5-dichloropyrid-4-yl)-3-cyclopent-2-enyloxy-4-methoxybenzamide(1 g) (mean particle size 3.5 microns) and lactose (99 g) (mean particlesize 72 microns) are blended together for 30 minutes in a mechanicalshaker/mixer. The resulting blend is filled, to a fill weight of 25 mg,into No. 3 hard gelatin capsules, to give a product suitable for use,for example, with a dry powder inhaler.

COMPOSITION EXAMPLE 7

    ______________________________________                                        No. 2 size gelatin capsules each containing:                                  ______________________________________                                        (±)-N-(3,5-dichloropyrid-4-yl)-3-cyclopent-                                                          20     mg                                           2-enyloxy-4-methoxybenzamide                                                  lactose                   100    mg                                           starch                    60     mg                                           dextrin                   40     mg                                           magnesium stearate        1      mg                                           ______________________________________                                    

are prepared in accordance with the usual procedure.

COMPOSITION EXAMPLE 8

N-(3,5-Dichloropyrid-4-yl)-3-cyclopentyloxy-4-difluoromethoxybenzamide(1 g) (mean particle size 3.5 microns) and lactose (99 g) (mean particlesize 72 microns) are blended together for 30 minutes in a mechanicalshaker/mixer. The resulting blend is filled, to a fill weight of 25 mg,into No. 3 hard gelatin capsules, to give a product suitable for use,for example, with a dry powder inhaler.

COMPOSITION EXAMPLE 9

    ______________________________________                                        No. 2 size gelatin capsules each containing:                                  ______________________________________                                        N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-                                                          20     mg                                           difluoromethoxybenzamide                                                      lactose                   100    mg                                           starch                    60     mg                                           dextrin                   40     mg                                           magnesium stearate        1      mg                                           ______________________________________                                    

are prepared in accordance with the usual procedure.

COMPOSITION EXAMPLE 10

3-Cyclopentyloxy-4-methoxyphenyl-2',6'-dichlorobenzyl ketone (1 g) (meanparticle size 3.5 microns) and lactose (99 g) (mean particle size 72microns) are blended together for minutes in a mechanical shaker/mixer.The resulting blend is filled, to a fill weight of 25 mg, into No. 3hard gelatin capsules, to give a product suitable for use, for example,with a dry powder inhaler.

COMPOSITION EXAMPLE 11

3-Cyclopentyloxy-4-methoxyphenyl-3,5-dichloropyrid-4-ylmethyl ketone (1g) (mean particle size 3.5 microns) and lactose (99 g) (mean particlesize 72 microns) are blended together for 30 minutes in a mechanicalshaker/mixer. The resulting blend is filled, to a fill weight of 25 mg,into No. 3 hard gelatin capsules, to give a product suitable for use,for example, with a dry powder inhaler.

COMPOSITION EXAMPLE 12

    ______________________________________                                        No. 2 size gelatin capsules each containing:                                  ______________________________________                                        3-cyclopentyloxy-4-methoxyphenyl-2',6'-                                                                20     mg                                            dichlorobenzyl ketone                                                         lactose                  100    mg                                            starch                   60     mg                                            dextrin                  40     mg                                            magnesium stearate       1      mg                                            ______________________________________                                    

are prepared in accordance with the usual procedure.

COMPOSITION EXAMPLE 13

    ______________________________________                                        No. 2 size gelatin capsules each containing:                                  ______________________________________                                        3-cyclopentyloxy-4-methoxyphenyl-3,5-dichloropyrid-4-                                                   20      mg                                          ylmethyl ketone                                                               lactose                   100     mg                                          starch                    60      mg                                          dextrin                   40      mg                                          magnesium stearate        1       mg                                          ______________________________________                                    

are prepared in accordance with the usual procedure.

COMPOSITION EXAMPLE 14

3-Cyclopentyloxy-4-methoxyphenyl-2',6'-dichlorobenzyl ketone (1 g) (meanparticle size 3.5 microns) and lactose (99 g) (mean particle size 72microns) are blended together for 30 minutes in a mechanicalshaker/mixer. The resulting blend is filled, to a fill weight of 25 mg,into No. 3 hard gelatin capsules, to give a product suitable for use,for example, with a dry powder inhaler.

COMPOSITION EXAMPLE 15

3-Cyclopentyloxy-4-methoxyphenyl 3,5-dichloropyrid-4-ylmethyl ketone (1g) (mean particle size 3.5 microns) and lactose (99 g) (mean particlesize 72 microns) are blended together for 30 minutes in a mechanicalshaker/mixer. The resulting blend is filled, to a fill weight of 25 mg,into No. 3 hard gelatin capsules, to give a product suitable for use,for example, with a dry powder inhaler.

COMPOSITION EXAMPLE 16

    ______________________________________                                        No. 2 size gelatin capsules each containing:                                  ______________________________________                                        3-cyclopentyloxy-4-methoxyphenyl-2'-6'-                                                                20     mg                                            dichlorobenzyl ketone                                                         lactose                  100    mg                                            starch                   60     mg                                            dextrin                  40     mg                                            magnesium stearate       1      mg                                            ______________________________________                                    

are prepared in accordance with the usual procedure.

COMPOSITION EXAMPLE 17

    ______________________________________                                        No. 2 size gelatin capsules each containing:                                  ______________________________________                                        3-cyclopentyloxy-4-methoxyphenyl-3,5-dichloropyrid-4-                                                   20      mg                                          ylmethyl ketone                                                               lactose                   100     mg                                          starch                    60      mg                                          dextrin                   40      mg                                          magnesium stearate        1       mg                                          ______________________________________                                    

are prepared in accordance with the usual procedure.

COMPOSITION EXAMPLE 18

3-Cyclopentyloxy-4-methoxyphenyl-2,6-dichlorobenzamide (1 g) (meanparticle size 3.5 microns) and lactose (99 g) (mean particle size 72microns) are blended together for 30 minutes in a mechanicalshaker/mixer. The resulting blend is filled, to a fill weight of 25 mg,into No. 3 hard gelatin capsules, to give a product suitable for use,for example, with a dry powder inhaler.

Similar compositions are prepared from other compounds of formula I.

COMPOSITION EXAMPLE 19

    ______________________________________                                        No. 2 size gelatin capsules each containing:                                  ______________________________________                                        3-cyclopentyloxy-4-methoxyphenyl-2,6-dichlorobenzamide                                                   20     mg                                          lactose                    100    mg                                          starch                     60     mg                                          dextrin                    40     mg                                          magnesium stearate         1      mg                                          ______________________________________                                    

are prepared in accordance with the usual procedure.

Similar compositions are prepared from other compounds of formula I.

COMPOSITION EXAMPLE 20

N-(3,5-difluoropyrid-4-yl)-3-cyclopentyloxy-4-metboxybenzamide (1 g)(mean particle size 3.5 microns) and lactose (99 g) (mean particle size72 microns) are blended together for 30 minutes in a mechanicalshaker/mixer. The resulting blend is filled, to a fill weight of 25 mg,into No. 3 hard gelatin capsules, to give a product suitable for use,for example, with a dry powder inhaler.

COMPOSITION EXAMPLE 21

    ______________________________________                                        No. 2 size gelatin capsules each containing:                                  ______________________________________                                        N-(3,5-difluoropyrid-4-yl)-3-cyclopentyloxy-4-                                                          20     mg                                           methoxybenzamide                                                              lactose                   100    mg                                           starch                    60     mg                                           dextrin                   40     mg                                           magnesium stearate        1      mg                                           ______________________________________                                    

are prepared in accordance with the usual procedure.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof.

What is claimed is:
 1. A method for treating an inflammatory disease oran autoimmune disease capable of being modulated by inhibiting TNF, saidmethod comprising administering to a patient suffering from said diseasean effective amount of a compound of formula I ##STR36## wherein R¹ isoptionally substituted lower alkyl;R² is optionally substitutedcycloalkyl, optionally substituted cycloalkenyl, optionally substitutedor oxidized cyclothioalkyl or optionally substituted or oxidizedcyclothioalkenyl; R³ is optionally substituted aryl or optionallysubstituted pyridyl; Z, Z¹ and Z² are independently oxygen or sulfur;and Z³ is --CZNH--, or an N-oxide thereof, a hydrate thereof or apharmaceutically acceptable salt thereof.
 2. The method of claim 1wherein the disease state is selected from the group consisting of jointinflammation, arthritis, rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, acute respiratory distress syndrome and asthma.
 3. Themethod of claim 2 wherein the disease state is joint inflammation.
 4. Amethod for treating an inflammatory disease capable of being modulatedby inhibiting production of cyclic AMP phosphodiesterase, said methodcomprising administering to a patient suffering from said disease aneffective amount of a compound of formula I ##STR37## wherein R¹ isoptionally substituted lower alkyl;R² is optionally substitutedcycloalkyl, optionally substituted cycloalkenyl, optionally substitutedor oxidized cyclothioalkyl or optionally substituted or oxidizedcyclothioalkenyl; R³ is optionally substituted aryl or optionallysubstituted pyridyl; Z, Z¹ and Z² are independently oxygen or sulfur;and Z³ is --CZNH--, or an N-oxide thereof, a hydrate thereof or apharmaceutically acceptable salt thereof.
 5. The method of claim 4wherein the inflammatory disease is asthma, allergic rhinitis, rheumaticarthritis, or adult respiratory distress syndrome.
 6. The method ofclaim 5 wherein the inflammatory disease is asthma.